Therapeutic compounds and uses thereof

ABSTRACT

The present invention relates to compounds of formula (I): 
                         
and to salts thereof, wherein R 1 , R 2 , R c , and R d  have any of the values defined in the specification, and compositions and uses thereof. The compounds are useful as inhibitors of bromodomains. Also included are pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and methods of using such compounds and salts in the treatment of various bromodomain-mediated disorders.

CROSS-REFERENCE TO RELATED APPLICATION(S)

This patent application is a continuation of International Application No. PCT/US2015/059997, filed Nov. 10, 2015, which claims the benefit of priority of U.S. application Ser. No. 62/077,711, filed Nov. 10, 2014, which applications are herein incorporated by reference.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to compounds useful as inhibitors of bromodomains.

BACKGROUND OF THE INVENTION

Chromatin is a complex combination of DNA and protein that makes up chromosomes. It is found inside the nuclei of eukaryotic cells and is divided between heterochromatin (condensed) and euchromatin (extended) forms. The major components of chromatin are DNA and proteins. Histones are the chief protein components of chromatin, acting as spools around which DNA winds. The functions of chromatin are to package DNA into a smaller volume to fit in the cell, to strengthen the DNA to allow mitosis and meiosis, and to serve as a mechanism to control expression and DNA replication. The chromatin structure is controlled by a series of post-translational modifications to histone proteins, notably histones H3 and H4, and most commonly within the “histone tails” which extend beyond the core nucleosome structure. Histone tails tend to be free for protein-protein interaction and are also the portion of the histone most prone to post-translational modification. These modifications include acetylation, methylation, phosphorylation, ubiquitinylation, and SUMOylation. These epigenetic marks are written and erased by specific enzymes that place the tags on specific residues within the histone tail, thereby forming an epigenetic code, which is then interpreted by the cell to allow gene specific regulation of chromatin structure and thereby transcription.

Of all classes of proteins, histones are amongst the most susceptible to post-translational modification. Histone modifications are dynamic, as they can be added or removed in response to specific stimuli, and these modifications direct both structural changes to chromatin and alterations in gene transcription. Distinct classes of enzymes, namely histone acetyltransferases (HATs) and histone deacetylases (HDACs), acetylate or de-acetylate specific histone lysine residues (Struhl K., Genes Dev., 1989, 12, 5, 599-606).

Bromodomains, which are approximately 110 amino acids long, are found in a large number of chromatin-associated proteins and have been identified in approximately 70 human proteins, often adjacent to other protein motifs (Jeanmougin F., et al., Trends Biochem. Sci., 1997, 22, 5, 151-153; and Tamkun J. W., et al., Cell, 1992, 7, 3, 561-572). Interactions between bromodomains and modified histones may be an important mechanism underlying chromatin structural changes and gene regulation. Bromodomain-containing proteins have been implicated in disease processes including cancer, inflammation and viral replication. See, e.g., Prinjha et al., Trends Pharm. Sci., 33(3):146-153 (2012) and Muller et al., Expert Rev., 13(29):1-20 (September 2011).

Cell-type specificity and proper tissue functionality requires the tight control of distinct transcriptional programs that are intimately influenced by their environment. Alterations to this transcriptional homeostasis are directly associated with numerous disease states, most notably cancer, immuno-inflammation, neurological disorders, and metabolic diseases. Bromodomains reside within key chromatin modifying complexes that serve to control distinctive disease-associated transcriptional pathways. This is highlighted by the observation that mutations in bromodomain-containing proteins are linked to cancer, as well as immune and neurologic dysfunction. Moreover, recent findings have demonstrated that small molecule inhibition of the bromodomains of BRD4 may have clinical utility in diverse human diseases, ranging from auto-immunity to cardiac hypertrophy. This is possible because the underlying mechanism resides in transcriptional regulation. Hence, the selective inhibition of bromodomains across the family creates varied opportunities as novel therapeutic agents in human dysfunction.

There is a need for treatments for cancer, immunological disorders, and other bromodomain related diseases.

SUMMARY OF THE INVENTION

One aspect includes a compound of formula (I):

or a salt thereof, wherein:

R¹ is H, C₁₋₁₂alkyl, C₂₋₁₂alkenyl, C₂₋₁₂alkynyl, or carbocyclyl, wherein each C₁₋₁₂alkyl, C₂₋₁₂alkenyl, C₂₋₁₂alkynyl, and carbocyclyl of R¹ is optionally substituted with one or more groups R^(a);

R² is H, C₁₋₁₂alkyl, C₂₋₁₂alkenyl, C₂₋₁₂alkynyl, or C₃₋₈cycloalkyl, wherein each C₁₋₁₂alkyl, C₂₋₁₂alkenyl, C₂₋₁₂alkynyl, and C₃₋₈cycloalkyl of R² is optionally substituted with one or more groups R^(b); and

each R^(a) is independently selected from oxo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, carbocyclyl, heterocyclyl, —F, —Cl, —Br, —I, —NO₂, —N(R^(v))₂, —CN, —C(O)—N(R^(v))₂, —S(O)—N(R^(v))₂, —S(O)₂—N(R^(v))₂, —O—R^(v), —S—R^(v), —O—C(O)—R^(v), —O—C(O)—O—R^(v), —C(O)—R^(v), —C(O)—O—R^(v), —S(O)—R^(v), —S(O)₂—R^(v), —O—C(O)—N(R^(v))₂, —N(R^(v))—C(O)—OR^(v), —N(R^(v))—C(O)—N(R^(v))₂, —N(R^(v))—C(O)—R^(v), —N(R^(v))—S(O)—R^(v), —N(R^(v))—S(O)₂—R^(v), —N(R^(v))—S(O)—N(R^(v))₂, and —N(R^(v))—S(O)₂—N(R^(v))₂, wherein any C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, carbocyclyl, and heterocyclyl, is optionally substituted with one or more groups independently selected from oxo, halo, —NO₂, —N(R^(v))₂, —CN, —C(O)—N(R^(v))₂, —S(O)—N(R^(v))₂, —S(O)₂—N(R^(v))₂, —O—R^(v), —S—R^(v), —O—C(O)—R^(v), —C(O)—R^(v), —C(O)—O—R^(v), —S(O)—R^(v), —S(O)₂—R^(v), —C(O)—N(R^(v))₂, —N(R^(v))—C(O)—R^(v), —N(R^(v))—S(O)—R^(v), —N(R^(v))—S(O)₂—R^(v) and C₁₋₆alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;

each R^(b) is independently selected from oxo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, carbocyclyl, heterocyclyl, —F, —Cl, —Br, —I, —NO₂, —N(R^(w))₂, —CN, —C(O)—N(R^(w))₂, —S(O)—N(R^(w))₂, —S(O)₂—N(R^(w))₂, —O—R^(w), —S—R^(w), —O—C(O)—R^(w), —O—C(O)—O—R^(w), —C(O)—R^(w), —C(O)—O—R^(w), —S(O)—R^(w), —S(O)₂—R^(w), —O—C(O)—N(R^(w))₂, —N(R^(w))—C(O)—OR^(w), —N(R^(w))—C(O)—N(R^(w))₂, —N(R^(w))—C(O)—R^(w), —N(R^(w))—S(O)—R^(w), —N(R^(w))—S(O)₂—R^(w), —N(R^(w))—S(O)—N(R^(w))₂, and —N(R^(w))—S(O)₂—N(R^(w))₂, wherein any C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, —NO₂, —N(R^(w))₂, —CN, —C(O)—N(R^(w))₂, —S(O)—N(R^(w))₂, —S(O)₂—N(R^(w))₂, —O—R^(w), —S—R^(w), —O—C(O)—R^(w), —C(O)—R^(w), —C(O)—O—R^(w), —S(O)—R^(w), —S(O)₂—R^(w), —C(O)—N(R^(w))₂, —N(R^(w))—C(O)—R^(w), —N(R^(w))—S(O)—R^(w), —N(R^(w))—S(O)₂—R^(w) and C₁₋₆alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;

each R^(c) and R^(d) is independently selected from hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl, wherein each C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more substituent groups independently selected from oxo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, heterocyclyl, —F, —Cl, —Br, —I, —NO₂, —N(R^(v))₂, —CN, —C(O)—N(R^(h))₂, —S(O)—N(R^(h))₂, —S(O)₂—N(R^(h))₂, —O—R^(h), —S—R^(h), —O—C(O)—R^(h), —O—C(O)—O—R^(h), —C(O)—R^(h), —C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h), —O—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—OR^(h), —N(R^(h))—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)—R^(h), —N(R^(h))—S(O)₂—R^(h), —N(R^(h))—S(O)—N(R^(h))₂, and —N(R^(h))—S(O)₂—N(R^(h))₂, wherein any C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl of the substituent groups, is optionally substituted with one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, —NO₂, —N(R^(h))₂, —CN, —C(O)—N(R^(h))₂, —S(O)—N(R^(h))₂, —S(O)₂—N(R^(h))₂, —O—R^(h), —S—R^(h), —O—C(O)—R^(h), —C(O)—R^(h), —C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h), —C(O)—N(R^(h))₂, —N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)—R^(h), —N(R^(h))—S(O)₂—R^(h), and C₁₋₆alkyl, which heterocyclyl, carbocyclyl and C₁₋₆alkyl are optionally substituted with one or more groups independently selected from oxo, halo, C₁₋₆alkyl, cyano, —O—R^(h), heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C₁₋₆alkyl;

or R^(c) and R^(d) are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, heterocyclyl, —F, —Cl, —Br, —I, —NO₂, —N(R^(v))₂, —CN, —C(O)—N(R^(h))₂, —S(O)—N(R^(h))₂, —S(O)₂—N(R^(h))₂, —O—R^(h), —S—R^(h), —O—C(O)—R^(h), —O—C(O)—O—R^(h), —C(O)—R^(h), —C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h), —O—C(O)—N(R^(h))₂, —N(R^(h))C(O)OR^(h), —N(R^(h))—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)—R^(h), —N(R^(h))—S(O)₂—R^(h), —N(R^(h))—S(O)—N(R^(h))₂, and —N(R^(h))—S(O)₂—N(R^(h))₂, wherein any C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from C₁₋₆alkyl, carbocyclyl, heterocyclyl, —F, —Cl, —Br, —I, —NO₂, —N(R^(h))₂, —CN, —C(O)—N(R^(h))₂, —S(O)—N(R^(h))₂, —S(O)₂—N(R^(h))₂, —O—R^(h), —S—R^(h), —O—C(O)—R^(h), —O—C(O)—O—R^(h), —C(O)—R^(h), —C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h), —O—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—OR^(h), —N(R^(h))—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)—R^(h), —N(R^(h))—S(O)₂—R^(h), —N(R^(h))—S(O)—N(R^(h))₂, and —N(R^(h))—S(O)₂—N(R^(h))₂, which C₁₋₆alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more groups independently selected from halo and C₁₋₆alkyl;

each R^(h) is independently selected from hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl, wherein each C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, carbocyclyl, heterocyclyl, and C₁-C₆ alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two R^(h) are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C₁₋₃alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;

each R^(v) is independently selected from hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl, wherein each C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, and C₁-C₆ alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two R^(v) are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C₁₋₃alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; and

each R^(w) is independently selected from hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl, wherein each C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, and C₁-C₆ alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two R^(w) are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C₁₋₃alkyl that is optionally substituted with one or more groups independently selected from oxo and halo.

Another aspect includes a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, carrier, or vehicle.

Another aspect includes a method for treating a bromodomain-mediated disorder in an animal (e.g., a mammal such as a human) comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof to the animal.

Another aspect includes a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in medical therapy.

Another aspect includes a compound of formula (I) or a pharmaceutically acceptable salt thereof for the prophylactic or therapeutic treatment of a bromodomain-mediated disorder.

Another aspect includes the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof to prepare a medicament for treating a bromodomain-mediated disorder in an animal (e.g., a mammal such as a human).

Another aspect includes compounds for the study of bromodomains.

Another aspect includes synthetic intermediates and synthetic processes disclosed herein that are useful for preparing a compound of formula (I) or a salt thereof.

DETAILED DESCRIPTION

Compounds and Definitions

Definitions and terms are described in more detail below. Chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75^(th) Ed.

Unless otherwise stated, compounds of formula I include enantiomeric, diastereomeric and geometric (or conformational) isomeric forms of a given structure. For example, the R and S configurations for each asymmetric center, Z and E double bond isomers, Z and E conformational isomers, single stereochemical isomers, as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures are included. Unless otherwise stated, all tautomeric forms of structures depicted herein are included. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds of formula I, wherein the independent replacement or enrichment of one or more hydrogen by deuterium or tritium, carbon by ¹³C- or ¹⁴C carbon, nitrogen by a ¹⁵N nitrogen, sulfur by a ³³S, ³⁴S or ³⁶S sulfur, or oxygen by a ¹⁷O or ¹⁸O oxygen are included. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents.

Where a particular enantiomer is described, it may, in certain embodiments be provided substantially free of the corresponding enantiomer, and may also be referred to as “optically enriched.” “Optically-enriched,” as used herein, means that the mixture of enantiomers is made up of a significantly greater proportion of one enantiomer, and may be described by enantiomeric excess (ee %). In certain embodiments, the mixture of enantiomers is made up of at least about 90% by weight of a given enantiomer (about 90% ee). In other embodiments, the mixture of enantiomers is made up of at least about 95%, 98% or 99% by weight of a given enantiomer (about 95%, 98% or 99% ee). Enantiomers and diastereomers may be isolated from racemic mixtures by any method known to those skilled in the art, including recrystallization from solvents in which one stereoisomer is more soluble than the other, chiral high pressure liquid chromatography (HPLC), supercritical fluid chromatography (SFC), the formation and crystallization of chiral salts, which are then separated by any of the above methods, or prepared by asymmetric syntheses and optionally further enriched. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, et al., Tetrahedron 33:2725 (1977); Eliel, E. L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, S. H. Tables of Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind. 1972).

The term “heteroatom” means any atom independently selected from an atom other than carbon or hydrogen, for example, one or more of oxygen, sulfur, nitrogen, phosphorus or silicon (including any oxidized form of nitrogen, sulfur, phosphorus or silicon; and the quaternized form of any nitrogen).

The terms “halo” and “halogen” as used herein refer to an atom selected from fluorine (fluoro, —F), chlorine (chloro, —Cl), bromine (bromo, —Br) and iodine (iodo, —I).

The term “oxo” refers to ═O or (═O)₂.

The term “unsaturated”, as used herein, means that a moiety has one or more units of unsaturation.

The term “carbocyclyl” used alone or as part of a larger moiety, refers to a saturated, partially unsaturated, or aromatic ring system having 3 to 20 carbon atoms. In one embodiment, carbocyclyl includes 3 to 12 carbon atoms (C₃-C₁₂). In another embodiment, carbocyclyl includes C₃-C₈, C₃-C₁₀ or C₅-C₁₀. In other embodiment, carbocyclyl, as a monocycle, includes C₃-C₈, C₃-C₆ or C₅-C₆. In another embodiment, carbocyclyl, as a bicycle, includes C₇-C₁₂. In another embodiment, carbocyclyl, as a spiro system, includes C₅-C₁₂. Examples of monocyclic carbocyclyls include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, perdeuteriocyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, phenyl, and cyclododecyl; bicyclic carbocyclyls having 7 to 12 ring atoms include [4,3], [4,4], [4,5], [5,5], [5,6] or [6,6] ring systems, for example bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, naphthalene, and bicyclo[3.2.2]nonane; and spiro carbocyclyls include spiro[2.2]pentane, spiro[2.3]hexane, spiro[2.4]heptane, spiro[2.5]octane and spiro[4.5]decane. The term carbocyclyl includes aryl ring systems as defined herein. The term carbocycyl also includes cycloalkyl rings (e.g. saturated or partially unsaturated mono-, bi-, or spiro-carbocycles).

The term “alkyl,” as used herein, refers to a saturated linear or branched-chain monovalent hydrocarbon radical. In one embodiment, the alkyl radical is one to eighteen carbon atoms (C₁-C₁₈). In other embodiments, the alkyl radical is C₀-C₆, C₀-C₅, C₀-C₃, C₁-C₁₂, C₁-C₁₀, C₁-C₈, C₁-C₆, C₁-C₅, C₁-C₄ or C₁-C₃. C₀ alkyl refers to a bond. Examples of alkyl groups include methyl (Me, —CH₃), ethyl (Et, —CH₂CH₃), 1-propyl (n-Pr, n-propyl, —CH₂CH₂CH₃), 2-propyl (i-Pr, i-propyl, —CH(CH₃)₂), 1-butyl (n-Bu, n-butyl, —CH₂CH₂CH₂CH₃), 2-methyl-1-propyl (i-Bu, i-butyl, —CH₂CH(CH₃)₂), 2-butyl (s-Bu, s-butyl, —CH(CH₃)CH₂CH₃), 2-methyl-2-propyl (t-Bu, t-butyl, —C(CH₃)₃), 1-pentyl (n-pentyl, —CH₂CH₂CH₂CH₂CH₃), 2-pentyl (—CH(CH₃)CH₂CH₂CH₃), 3-pentyl (—CH(CH₂CH₃)₂), 2-methyl-2-butyl (—C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl (—CH(CH₃)CH(CH₃)₂), 3-methyl-1-butyl (—CH₂CH₂CH(CH₃)₂), 2-methyl-1-butyl (—CH₂CH(CH₃)CH₂CH₃), 1-hexyl (—CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl (—CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl (—CH(CH₂CH₃)(CH₂CH₂CH₃)), 2-methyl-2-pentyl (—C(CH₃)₂CH₂CH₂CH₃), 3-methyl-2-pentyl (—CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl (—CH(CH₃)CH₂CH(CH₃)₂), 3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂), 2-methyl-3-pentyl (—CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl (—C(CH₃)₂CH(CH₃)₂), 3,3-dimethyl-2-butyl (—CH(CH₃)C(CH₃)₃, heptyl, octyl, nonyl, decyl, undecyl and dodecyl.

The term “alkenyl,” as used herein, denotes a linear or branched-chain monovalent hydrocarbon radical with at least one carbon-carbon double bond. An alkenyl includes radicals having “cis” and “trans” orientations, or alternatively, “E” and “Z” orientations. In one example, the alkenyl radical is two to eighteen carbon atoms (C₂-C₁₈). In other examples, the alkenyl radical is C₂-C₁₂, C₂-C₁₀, C₂-C₈, C₂-C₆ or C₂-C₃. Examples include, but are not limited to, ethenyl or vinyl (—CH═CH₂), prop-1-enyl (—CH═CHCH₃), prop-2-enyl (—CH₂CH═CH₂), 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3-diene, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl and hexa-1,3-dienyl.

The term “alkynyl,” as used herein, refers to a linear or branched monovalent hydrocarbon radical with at least one carbon-carbon triple bond. In one example, the alkynyl radical is two to eighteen carbon atoms (C₂-C₁₈). In other examples, the alkynyl radical is C₂-C₁₂, C₂-C₁₀, C₂-C₈, C₂-C₆ or C₂-C₃. Examples include, but are not limited to, ethynyl (—C≡CH), prop-1-ynyl (—C≡CCH₃), prop-2-ynyl (propargyl, —CH₂C≡CH), but-1-ynyl, but-2-ynyl and but-3-ynyl.

The term “alkoxy” refers to a linear or branched monovalent radical represented by the formula —OR in which R is alkyl, alkenyl, alkynyl or carbocycyl. Alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, and cyclopropoxy.

The term “haloalkyl,” as used herein, refers to an alkyl as defined herein that is substituted with one or more (e.g. 1, 2, 3, or 4) halo groups.

The term “aryl” used alone or as part of a larger moiety as in “arylalkyl”, “arylalkoxy”, or “aryloxyalkyl”, refers to a monocyclic, bicyclic or tricyclic, carbon ring system, that includes fused rings, wherein at least one ring in the system is aromatic. The term “aryl” may be used interchangeably with the term “aryl ring”. In one embodiment, aryl includes groups having 6-18 carbon atoms. In another embodiment, aryl includes groups having 6-10 carbon atoms. Examples of aryl groups include phenyl, naphthyl, anthracyl, biphenyl, phenanthrenyl, naphthacenyl, 1,2,3,4-tetrahydronaphthalenyl, 1H-indenyl, 2,3-dihydro-1H-indenyl, and the like, which may be substituted or independently substituted by one or more substituents described herein. A particular aryl is phenyl. In another embodiment aryl includes an aryl ring fused to one or more carbocyclic rings, such as indanyl, naphthimidyl, or tetrahydronaphthyl, and the like, where the radical or point of attachment is on an aromatic ring.

The term “heteroaryl” used alone or as part of a larger moiety, e.g., “heteroarylalkyl”, or “heteroarylalkoxy”, refers to a monocyclic, bicyclic or tricyclic ring system having 5 to 14 ring atoms, wherein at least one ring is aromatic and contains at least one heteroatom. In one embodiment, heteroaryl includes 4-6 membered monocyclic aromatic groups where one or more ring atoms is nitrogen, sulfur or oxygen that is independently optionally substituted. In another embodiment, heteroaryl includes 5-6 membered monocyclic aromatic groups where one or more ring atoms is nitrogen, sulfur or oxygen that is independently optionally substituted. Example heteroaryl groups include thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl, tetrazolo[1,5-b]pyridazinyl, imidazol[1,2-a]pyrimidinyl, purinyl, benzoxazolyl, benzofuryl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzoimidazolyl, indolyl, 1,3-thiazol-2-yl, 1,3,4-triazol-5-yl, 1,3-oxazol-2-yl, 1,3,4-oxadiazol-5-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-thiadiazol-5-yl, 1H-tetrazol-5-yl, 1,2,3-triazol-5-yl, and pyrid-2-yl N-oxide. The terms “heteroaryl” also includes groups in which a heteroaryl is fused to one or more aryl, carbocyclyl, or heterocyclyl rings, where the radical or point of attachment is on the heteroaryl ring. Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. A heteroaryl group may be mono-, bi- or tri-cyclic.

As used herein, the term “heterocyclyl” refers to a “carbocyclyl” as defined herein, wherein one or more (e.g. 1, 2, 3, or 4) carbon atoms have been replaced with a heteroatom (e.g. O, N, or S). In some embodiments, a heterocyclyl refers to a saturated ring system, such as a 3 to 12 membered saturated heterocyclyl ring system. In some embodiments, a heterocyclyl refers to a heteroaryl ring system, such as a 5 to 14 membered heteroaryl ring system. A heterocyclyl can optionally be substituted with one or more substituents independently selected from those defined herein.

In one example, heterocyclyl includes 3-12 ring atoms and includes monocycles, bicycles, tricycles and spiro ring systems, wherein the ring atoms are carbon, and one to five ring atoms is a heteroatom selected from nitrogen, sulfur or oxygen, which is independently optionally substituted by one or more groups. In one example, heterocyclyl includes 1 to 4 heteroatoms. In another example, heterocyclyl includes 3- to 7-membered monocycles having one or more heteroatoms selected from nitrogen, sulfur or oxygen. In another example, heterocyclyl includes 4- to 6-membered monocycles having one or more heteroatoms selected from nitrogen, sulfur or oxygen. In another example, heterocyclyl includes 3-membered monocycles. In another example, heterocyclyl includes 4-membered monocycles. In another example, heterocyclyl includes 5-6 membered monocycles. In one example, the heterocyclyl group includes 0 to 3 double bonds. Any nitrogen or sulfur heteroatom may optionally be oxidized (e.g. NO, SO, SO₂), and any nitrogen heteroatom may optionally be quaternized (e.g. [NR₄]⁺Cl⁻, [NR₄]⁺OH⁻). Example heterocyclyls include oxiranyl, aziridinyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, pyrrolidinyl, dihydro-1H-pyrrolyl, dihydrofuranyl, tetrahydrofuranyl, dihydrothienyl, tetrahydrothienyl, imidazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, dihydropyranyl, tetrahydropyranyl, hexahydrothiopyranyl, hexahydropyrimidinyl, oxazinanyl, thiazinanyl, thioxanyl, homopiperazinyl, homopiperidinyl, azepanyl, oxepanyl, thiepanyl, oxazepinyl, oxazepanyl, diazepanyl, 1,4-diazepanyl, diazepinyl, thiazepinyl, thiazepanyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, isothiazolidinyl, 1,1-dioxoisothiazolidinonyl, oxazolidinonyl, imidazolidinonyl, 4,5,6,7-tetrahydro[2H]indazolyl, tetrahydrobenzoimidazolyl, 4,5,6,7-tetrahydrobenzo[d]imidazolyl, 1,6-dihydroimidazol[4,5-d]pyrrolo[2,3-b]pyridinyl, thiazinyl, oxazinyl, thiadiazinyl, oxadiazinyl, dithiazinyl, dioxazinyl, oxathiazinyl, thiatriazinyl, oxatriazinyl, dithiadiazinyl, imidazolinyl, dihydropyrimidyl, tetrahydropyrimidyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, thiapyranyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithianyl, dithiolanyl, pyrimidinonyl, pyrimidindionyl, pyrimidin-2,4-dionyl, piperazinonyl, piperazindionyl, pyrazolidinylimidazolinyl, 3-azabicyclo[3.1.0]hexanyl, 3,6-diazabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexanyl, 2-azabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1]octanyl, 2-azabicyclo[2.2.2]octanyl, 8-azabicyclo[2.2.2]octanyl, 7-oxabicyclo[2.2.1]heptane, azaspiro[3.5]nonanyl, azaspiro[2.5]octanyl, azaspiro[4.5]decanyl, 1-azaspiro[4.5]decan-2-only, azaspiro[5.5]undecanyl, tetrahydroindolyl, octahydroindolyl, tetrahydroisoindolyl, tetrahydroindazolyl, 1,1-dioxohexahydrothiopyranyl. Examples of 5-membered heterocyclyls containing a sulfur or oxygen atom and one to three nitrogen atoms are thiazolyl, including thiazol-2-yl and thiazol-2-yl N-oxide, thiadiazolyl, including 1,3,4-thiadiazol-5-yl and 1,2,4-thiadiazol-5-yl, oxazolyl, for example oxazol-2-yl, and oxadiazolyl, such as 1,3,4-oxadiazol-5-yl, and 1,2,4-oxadiazol-5-yl. Example 5-membered ring heterocyclyls containing 2 to 4 nitrogen atoms include imidazolyl, such as imidazol-2-yl; triazolyl, such as 1,3,4-triazol-5-yl; 1,2,3-triazol-5-yl, 1,2,4-triazol-5-yl, and tetrazolyl, such as 1H-tetrazol-5-yl. Example benzo-fused 5-membered heterocyclyls are benzoxazol-2-yl, benzthiazol-2-yl and benzimidazol-2-yl. Example 6-membered heterocyclyls contain one to three nitrogen atoms and optionally a sulfur or oxygen atom, for example pyridyl, such as pyrid-2-yl, pyrid-3-yl, and pyrid-4-yl; pyrimidyl, such as pyrimid-2-yl and pyrimid-4-yl; triazinyl, such as 1,3,4-triazin-2-yl and 1,3,5-triazin-4-yl; pyridazinyl, in particular pyridazin-3-yl, and pyrazinyl. The pyridine N-oxides and pyridazine N-oxides and the pyridyl, pyrimid-2-yl, pyrimid-4-yl, pyridazinyl and the 1,3,4-triazin-2-yl groups, are other example heterocyclyl groups.

As used herein, the term “partially unsaturated” refers to a ring moiety that includes at least one double or triple bond between ring atoms but the ring moiety is not aromatic.

As used herein, the term “inhibitor” refers to a compound that binds to and inhibits a bromodomain with measurable affinity and activity. In certain embodiments, an inhibitor has an IC₅₀ or binding constant of less about 50 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, or less than about 10 nM.

The terms “measurable affinity” and “measurably inhibit,” as used herein, refer to a measurable reduction in activity of a bromodomain between: (i) a sample comprising a compound of formula I or composition thereof and such bromodomain, and (ii) an equivalent sample comprising such bromodomain, in the absence of said compound, or composition thereof.

“Pharmaceutically acceptable salts” include both acid and base addition salts. It is to be understood that when a compound or Example herein is shown as a specific salt, the corresponding free-base, as well as other salts of the corresponding free-base (including pharmaceutically acceptable salts of the corresponding free-base) are contemplated.

“Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid and the like, and organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, maloneic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, salicyclic acid and the like.

“Pharmaceutically acceptable base addition salts” include those derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Particularly base addition salts are the ammonium, potassium, sodium, calcium and magnesium salts. Salts derived from pharmaceutically acceptable organic nontoxic bases includes salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, tromethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. Particular organic non-toxic bases are isopropylamine, diethylamine, ethanolamine, tromethamine, dicyclohexylamine, choline, and caffeine.

The term “tautomer” or “tautomeric form” refers to structural isomers of different energies which are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions by reorganization of some of the bonding electrons.

A “solvate” refers to an association or complex of one or more solvent molecules and a compound of the present invention. Examples of solvents include water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid and ethanolamine. The term “hydrate” refers to the complex where the solvent molecule is water.

“Therapeutically effective amount” refers to an amount of a compound of the present invention that (i) treats the particular disease, condition or disorder, (ii) attenuates, ameliorates or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition or disorder described herein. In the case of cancer, the therapeutically effective amount of the drug may reduce the number of cancer cells; reduce the tumor size; inhibit (i.e., slow to some extent and preferably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow to some extent and preferably stop) tumor metastasis; inhibit, to some extent, tumor growth; and/or relieve to some extent one or more of the symptoms associated with the cancer. For cancer therapy, efficacy can, for example, be measured by assessing the time to disease progression (TTP) and/or determining the response rate (RR). In the case of immunological disorders, the therapeutic effective amount is an amount sufficient to decrease or alleviate an allergic disorder, the symptoms of an autoimmune and/or inflammatory disease, or the symptoms of an acute inflammatory reaction (e.g. asthma). In some embodiments, a therapeutically effective amount is an amount of a chemical entity described herein sufficient to significantly decrease the activity or number of drug tolerant or drug tolerant persisting cancer cells.

“Treatment” (and variations such as “treat” or “treating”) refers to clinical intervention in an attempt to alter the natural course of the individual or cell being treated, and can be performed either for prophylaxis or during the course of clinical pathology. Desirable effects of treatment include one or more of preventing occurrence or recurrence of disease, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, stabilized (i.e., not worsening) state of disease, preventing metastasis, decreasing the rate of disease progression, amelioration or palliation of the disease state, prolonging survival as compared to expected survival if not receiving treatment and remission or improved prognosis. In certain embodiments, a compound of formula I is used to delay development of a disease or disorder or to slow the progression of a disease or disorder. Those individuals in need of treatment include those already with the condition or disorder as well as those prone to have the condition or disorder, (for example, through a genetic mutation or aberrant expression of a gene or protein) or those in which the condition or disorder is to be prevented.

As used herein, “a” or “an” means one or more, unless clearly indicated otherwise.

As used herein, “another” means at least a second or more.

Exemplary Values

It is to be understood that two or more of the following embodiments may be combined.

One embodiment provides a compound of formula I or a salt thereof, wherein:

R¹ is H, C₁₋₁₂alkyl, C₂₋₁₂alkenyl, C₂₋₁₂alkynyl, or carbocyclyl, wherein each C₁₋₁₂alkyl, C₂₋₁₂alkenyl, C₂₋₁₂alkynyl, and carbocyclyl of R¹ is optionally substituted with one or more groups R^(a);

R² is H, C₁₋₁₂alkyl, C₂₋₁₂alkenyl, C₂₋₁₂alkynyl, or C₃₋₈cycloalkyl, wherein each C₁₋₁₂alkyl, C₂₋₁₂alkenyl, C₂₋₁₂alkynyl, and C₃₋₈cycloalkyl of R² is optionally substituted with one or more groups R^(b); and

each R^(a) is independently selected from oxo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, carbocyclyl, heterocyclyl, —F, —Cl, —Br, —I, —NO₂, —N(R^(v))₂, —CN, —C(O)—N(R^(v))₂, —S(O)—N(R^(v))₂, —S(O)₂—N(R^(v))₂, —O—R^(v), —S—R^(v), —O—C(O)—R^(v), —O—C(O)—O—R^(v), —C(O)—R^(v), —C(O)—O—R^(v), —S(O)—R^(v), —S(O)₂—R^(v), —O—C(O)—N(R^(v))₂, —N(R^(v))—C(O)—OR^(v), —N(R^(v))—C(O)—N(R^(v))₂, —N(R^(v))—C(O)—R^(v), —N(R^(v))—S(O)—R^(v), —N(R^(v))—S(O)₂—R^(v), —N(R^(v))—S(O)—N(R^(v))₂, and —N(R^(v))—S(O)₂—N(R^(v))₂, wherein any C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, carbocyclyl, and heterocyclyl, is optionally substituted with one or more groups independently selected from oxo, halo, —NO₂, —N(R^(v))₂, —CN, —C(O)—N(R^(v))₂, —S(O)—N(R^(v))₂, —S(O)₂—N(R^(v))₂, —O—R^(v), —S—R^(v), —O—C(O)—R^(v), —C(O)—R^(v), —C(O)—O—R^(v), —S(O)—R^(v), —S(O)₂—R^(v), —C(O)—N(R^(v))₂, —N(R^(v))—C(O)—R^(v), —N(R^(v))—S(O)—R^(v), —N(R^(v))—S(O)₂—R^(v) and C₁₋₆alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;

each R^(b) is independently selected from oxo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, carbocyclyl, heterocyclyl, —F, —Cl, —Br, —I, —NO₂, —N(R^(w))₂, —CN, —C(O)—N(R^(w))₂, —S(O)—N(R^(w))₂, —S(O)₂—N(R^(w))₂, —O—R^(w), —S—R^(w), —O—C(O)—R^(w), —O—C(O)—O—R^(w), —C(O)—R^(w), —C(O)—O—R^(w), —S(O)—R^(w), —S(O)₂—R^(w), —O—C(O)—N(R^(w))₂, —N(R^(w))—C(O)—OR^(w), —N(R^(w))—C(O)—N(R^(w))₂, —N(R^(w))—C(O)—R^(w), —N(R^(w))—S(O)—R^(w), —N(R^(w))—S(O)₂—R^(w), —N(R^(w))—S(O)—N(R^(w))₂, and —N(R^(w))—S(O)₂—N(R^(w))₂, wherein any C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, —NO₂, —N(R^(w))₂—CN, —C(O)—N(R^(w))₂, —S(O)—N(R^(w))₂, —S(O)₂—N(R^(w))₂, —O—R^(w), —S—R^(w), —O—C(O)—R^(w), —C(O)—R^(w), —C(O)—O—R^(w), —S(O)—R^(w), —S(O)₂—R^(w), —C(O) N(R^(w))₂, —N(R^(w))—C(O)—R^(w), —N(R^(w))—S(O)—R^(w), —N(R^(w))—S(O)₂—R^(w) and C₁₋₆alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;

each R^(c) and R^(d) is independently selected from hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl, wherein each C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more substituent groups independently selected from oxo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, heterocyclyl, —F, —CI, —Br, —I, —NO₂, —N(R^(v))₂, —CN, —C(O)—N(R^(h))₂, —S(O)—N(R^(h))₂, —S(O)₂—N(R^(h))₂, —O—R^(h), —S—R^(h), —O—C(O)—R^(h), —O—C(O)—O—R^(h), —C(O)—R^(h), —C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h), —O—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—OR^(h), —N(R^(h))—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)—R^(h), —N(R^(h))—S(O)₂—R^(h), —N(R^(h))—S(O)—N(R^(h))₂, and —N(R^(h))—S(O)₂—N(R^(h))₂, wherein any C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl of the substituent groups, is optionally substituted with one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, —NO₂, —N(R^(h))₂, —CN, —C(O)—N(R^(h))₂, —S(O)—N(R^(h))₂, —S(O)₂—N(R^(h))₂, —O—R^(h), —S—R^(h), —O—C(O)—R^(h), —C(O)—R^(h), —C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h), —C(O)—N(R^(h))₂, —N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)—R^(h), —N(R^(h))—S(O)₂—R^(h), and C₁₋₆alkyl, which heterocyclyl, carbocyclyl and C₁₋₆alkyl are optionally substituted with one or more groups independently selected from oxo, halo, C₁₋₆alkyl, cyano, —O—R^(h), heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C₁₋₆alkyl;

or R^(c) and R^(d) are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, heterocyclyl, —F, —Cl, —Br, —I, —NO₂, —N(R^(v))₂, —CN, —C(O)—N(R^(h))₂, —S(O)—N(R^(h))₂, —S(O)₂—N(R^(h))₂, —O—R^(h), —S—R^(h), —O—C(O)—R^(h), —O—C(O)—O—R^(h), —C(O)—R^(h), —C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h), —O—C(O)—N(R^(h))₂, —N(R^(h))—C(O) OR^(h), —N(R^(h))—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)—R^(h), —N(R^(h))—S(O)₂—R^(h), —N(R^(h))—S(O)—N(R^(h))₂, and —N(R^(h))—S(O)₂—N(R^(h))₂, wherein any C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from C₁₋₆alkyl, carbocyclyl, heterocyclyl, —F, —Cl, —Br, —I, —NO₂, —N(R^(h))₂, —CN, —C(O)—N(R^(h))₂, —S(O)—N(R^(h))₂, —S(O)₂O—N(R^(h))₂, —O—R^(h), —S—R^(h), —O—C(O)—R^(h), —O—C(O)—O—R^(h), —C(O)—R^(h), —C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h), —O—C(O)—N(R^(h))₂, —N(R^(h))—C(O)OR^(h), —N(R^(h))—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)—R^(h), —N(R^(h))—S(O)₂—R^(h), —N(R^(h))—S(O)—N(R^(h))₂, and —N(R^(h))—S(O)₂—N(R^(h))₂, which C₁₋₆alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more groups independently selected from halo and C₁₋₆alkyl;

each R^(h) is independently selected from hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl, wherein each C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, carbocyclyl, heterocyclyl, and C₁-C₆ alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two R^(h) are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C₁₋₃alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;

each R^(v) is independently selected from hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl, wherein each C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, and C₁-C₆ alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two R^(v) are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C₁₋₃alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; and

each R^(w) is independently selected from hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl, wherein each C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, and C₁-C₆ alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two R^(w) are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C₁₋₃alkyl that is optionally substituted with one or more groups independently selected from oxo and halo.

One embodiment provides a compound of formula I or a salt thereof, wherein:

R¹ is H, C₁₋₁₂alkyl, C₂₋₁₂alkenyl, C₂₋₁₂alkynyl, or carbocyclyl, wherein each C₁₋₁₂alkyl, C₂₋₁₂alkenyl, C₂₋₁₂alkynyl, and carbocyclyl of R¹ is optionally substituted with one or more groups R^(a);

R² is H, C₁₋₁₂alkyl, C₂₋₁₂alkenyl, C₂₋₁₂alkynyl, or C₃₋₈cycloalkyl, wherein each C₁₋₁₂alkyl, C₂₋₁₂alkenyl, C₂₋₁₂alkynyl, and C₃₋₈cycloalkyl of R² is optionally substituted with one or more groups R^(b); and

each R^(a) is independently selected from oxo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, carbocyclyl, heterocyclyl, —F, —Cl, —Br, —I, —NO₂, —N(R^(v))₂, —CN, —C(O)—N(R^(v))₂, —S(O)—N(R^(v))₂, —S(O)₂—N(R^(v))₂, —O—R^(v), —S—R^(v), —O—C(O)—R^(v), —O—C(O)—O—R^(v), —C(O)—R^(v), —C(O)—O—R^(v), —S(O)—R^(v), —S(O)₂—R^(v), —O—C(O)—N(R^(v))₂, —N(R^(v))—C(O)—OR^(v), —N(R^(v))—C(O)—N(R^(v))₂, —N(R^(v))—C(O)—R^(v), —N(R^(v))—S(O)—R^(v), —N(R^(v))—S(O)₂—R^(v), —N(R^(v))—S(O)—N(R^(v))₂, and —N(R^(v))—S(O)₂—N(R^(v))₂, wherein any C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, carbocyclyl, and heterocyclyl, is optionally substituted with one or more groups independently selected from oxo, halo, —NO₂, —N(R^(v))₂, —CN, —C(O)—N(R^(v))₂, —S(O)—N(R^(v))₂, —S(O)₂—N(R^(v))₂, —O—R^(v), —S—R^(v), —O—C(O)—R^(v), —C(O)R^(v), —C(O)—O—R^(v), —S(O)—R^(v), —S(O)₂—R^(v), —C(O)—N(R^(v))₂, —N(R^(v))—C(O)—R^(v), —N(R^(v))—S(O)—R^(v), —N(R^(v))—S(O)₂—R^(v) and C₁₋₆alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;

each R^(b) is independently selected from oxo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, carbocyclyl, heterocyclyl, —F, —Cl, —Br, —I, —NO₂, —N(R^(w))₂, —CN, —C(O)—N(R^(w))₂, —S(O)—N(R^(w))₂, —S(O)₂—N(R^(w))₂, —O—R^(w), —S—R^(w), —O—C(O)—R^(w), —O—C(O)—O—R^(w), —C(O)—R^(w), —C(O)—O—R^(w), —S(O)—R^(w), —S(O)₂—R^(w), —O—C(O)—N(R^(w))₂, —N(R^(w))—C(O)—OR^(w), —N(R^(w))—C(O)—N(R^(w))₂, —N(R^(w))—C(O)—R^(w), —N(R^(w))—S(O)—R^(w), —N(R^(w))—S(O)₂—R^(w), —N(R^(w))—S(O)—N(R^(w))₂, and —N(R^(w))—S(O)₂—N(R^(w))₂, wherein any C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, —NO₂, —N(R^(w))₂, —CN, —C(O)—N(R^(w))₂, —S(O)—N(R^(w))₂, —S(O)₂—N(R^(w))₂, —O—R^(w), —S—R^(w), —O—C(O)—R^(w), —C(O)—R^(w), —C(O)—O—R^(w), —S(O)—R^(w), —S(O)₂—R^(w), —C(O)—N(R^(w))₂, —N(R^(w))—C(O)—R^(w), —N(R^(w))—S(O)—R^(w), —N(R^(w))—S(O)₂—R^(w) and C₁₋₆alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;

each R^(c) and R^(d) is independently selected from hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl, wherein each C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more substituent groups independently selected from oxo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, heterocyclyl, —F, —Cl, —Br, —I, —NO₂, —N(R^(v))₂, —CN, —C(O)—N(R^(h))₂, —S(O)—N(R^(h))₂, —S(O)₂—N(R^(h))₂, —O—R^(h), —S—R^(h), —O—C(O)—R^(h), —O—C(O)—O—R^(h), —C(O)—R^(h), —C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h), —O—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—OR^(h), —N(R^(h))—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)—R^(h), —N(R^(h))—S(O)₂—R^(h), —N(R^(h))—S(O)—N(R^(h))₂, and —N(R^(h))—S(O)₂—N(R^(h))₂, wherein any C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, carbocyclyl, and heterocyclyl of the substituent groups, is optionally substituted with one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, —NO₂, —N(R^(h))₂—CN, —C(O)—N(R^(h))₂, —S(O)—N(R^(h))₂, —S(O)₂—N(R^(h))₂—O—R^(h), —S—R^(h), —O—C(O)—R^(h), —C(O)—R^(h), —C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h), —C(O)—N(R^(h))₂, —N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)—R^(h), N(R^(h))—S(O)₂—R^(h), and C₁₋₆alkyl, which carbocyclyl and C₁₋₆alkyl are optionally substituted with one or more groups independently selected from oxo, halo, C₁₋₆alkyl, cyano, —O—R^(h), heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C₁₋₆alkyl;

or R^(c) and R^(d) are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, heterocyclyl, —F, —Cl, —Br, —I, —NO₂, —N(R^(v))₂, —CN, —C(O)—N(R^(h))₂, —S(O)—N(R^(h))₂, —S(O)₂—N(R^(h))₂, —O—R^(h), —S—R^(h), —O—C(O)—R^(h), —O—C(O)—O—R^(h), —C(O)—R^(h), —C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h), —O—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—R^(h), —N(R^(h))—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)—R^(h), —N(R^(h))—S(O)₂—R^(h), —N(R^(h))—S(O)—N(R^(h))₂, and —N(R^(h))—S(O)₂—N(R^(h))₂, wherein any C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from C₁₋₆alkyl, carbocyclyl, heterocyclyl, —F, —Cl, —Br, —I, —NO₂, —N(R^(h))₂, —CN, —C(O)—N(R^(h))₂, —S(O)—N(R^(h))₂, —S(O)₂—N(R^(h)), —O—R^(h), —S—R^(h), —O—C(O)—R^(h), —O—C(O)—O—R^(h), —C(O)—R^(h), —C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h), —O—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—OR^(h), —N(R^(h))—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)—R^(h), —N(R^(h))—S(O)₂—R^(h), —N(R^(h))—S(O)—N(R^(h))₂, and —N(R^(h))—S(O)₂—N(R^(h))₂, which C₁₋₆₆alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more groups independently selected from halo and C₁₋₆alkyl;

each R^(h) is independently selected from hydrogen, C₁₋₆₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl, wherein each C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, carbocyclyl, heterocyclyl, and C₁-C₆ alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two R^(h) are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C₁₋₃alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;

each R^(v) is independently selected from hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl, wherein each C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, and C₁-C₆ alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two R^(v) are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C₁₋₃alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; and

each R^(w) is independently selected from hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl, wherein each C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, and C₁-C₆ alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two R^(w) are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C₁₋₃alkyl that is optionally substituted with one or more groups independently selected from oxo and halo.

In certain embodiments R¹ is C₁₋₁₂alkyl or C₂₋₁₂alkenyl, wherein each C₁₋₁₂alkyl and C₂₋₁₂alkenyl is optionally substituted with one or more groups R^(a).

In certain embodiments R¹ is C₁₋₆alkyl or C₂₋₆alkenyl, wherein each C₁₋₆alkyl and C₂₋₆alkenyl is optionally substituted with one or more groups R^(a).

In certain embodiments R¹ is C₁₋₆alkyl or C₂₋₆alkenyl, wherein each C₁₋₆alkyl and C₂₋₆alkenyl is optionally substituted with one or more groups independently selected from carbocyclyl, heterocyclyl, —F, —Cl, —Br, —I, —N(R^(v))₂, —CN, —C(O)—N(R^(v))₂, —O—R^(v), —O—C(O)—R^(v), —C(O)—R^(v), and —C(O)—O—R^(v).

In certain embodiments R¹ is C₁₋₆alkyl or C₂₋₆alkenyl, wherein each C₁₋₆alkyl and C₂₋₆alkenyl is optionally substituted with one or more groups independently selected from carbocyclyl, —F, —Cl, —O—R^(v), —O—C(O)—R^(v), —C(O)—R^(v), and —C(O)—O—R^(v).

In certain embodiments R¹ is C₁₋₆alkyl or C₂₋₆alkenyl, wherein each C₁₋₆alkyl and C₂₋₆alkenyl is optionally substituted with one or more groups independently selected from C₃₋₆cycloalkyl.

In certain embodiments R¹ is methyl, butyl, 2-propenyl, 2-buten-1-yl, 3-buten-1-yl or 2-cyclopropylethyl.

In certain embodiments R² is H or C₁₋₁₂alkyl wherein each C₁₋₁₂alkyl is optionally substituted with one or more groups R^(b).

In certain embodiments R² is H or C₁₋₆alkyl wherein each C₁₋₁₂alkyl is optionally substituted with one or more groups R^(b).

In certain embodiments R² is H or C₁₋₆alkyl wherein each C₁₋₁₂alkyl is optionally substituted with one or more carbocyclyl, —F, —Cl, —O—R^(w), —O—C(O)—R^(w), —C(O)—R^(w), —C(O)—O—R^(w).

In certain embodiments R² is H or methyl.

In certain embodiments R² is H.

In certain embodiments R^(c) is hydrogen, C₁₋₆alkyl, or carbocyclyl, wherein each C₁₋₆alkyl and carbocyclyl is optionally substituted with one or more substituent groups independently selected from oxo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, heterocyclyl, —F, —Cl, —Br, —I, —NO₂, —N(R^(v))₂, —CN, —C(O)—N(R^(h))₂, —S(O)—N(R^(h))₂, —S(O)₂—N(R^(h))₂, —O—R^(h), —S—R^(h), —O—C(O)—R^(h), —O—C(O)—O—R^(h), —C(O)—R^(h), —C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h), —O—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—OR^(h), —N(R^(h)) —C(O) N(R^(h)), —N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)—R^(h), —N(R^(h))—S(O)₂—R^(h), —N(R^(h))—S(O)—N(R^(h))₂, and —N(R^(h))—S(O)₂—N(R^(h))₂, wherein any C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl of the substituent groups, is optionally substituted with one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, —NO₂, —N(R^(h))₂, —CN, —C(O)—N(R^(h))₂, —S(O)—N(R^(h))₂, —S(O)₂—N(R^(h))₂, —O—R^(h), —S—R^(h), —O—C(O)—R^(h), —C(O)—R^(h), —C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h), —C(O)—N(R^(h))₂, —N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)—R^(h), N(R^(h))—S(O)₂—R^(h), and C₁₋₆alkyl, which heterocyclyl, carbocyclyl and C₁₋₆alkyl are optionally substituted with one or more groups independently selected from oxo, halo, C₁₋₆alkyl cyano, —O—R^(h), heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo and C₁₋₆alkyl.

In certain embodiments R^(c) is hydrogen, C₁₋₆alkyl, or carbocyclyl, wherein each C₁₋₆alkyl and carbocyclyl is optionally substituted with one or more substituent groups independently selected from oxo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, heterocyclyl, —F, —Cl, —Br, —I, —NO₂, —N(R^(v))₂, —CN, —C(O)—N(R^(h))₂, —S(O)—N(R^(h))₂, —S(O)₂—N(R^(h))₂, —O—R^(h), —S—R^(h), —O—C(O)—R^(h), —O—C(O)—O—R^(h), —C(O)—R^(h), —C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h), —O—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—OR^(h), —N(R^(h))—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)—R^(h), —N(R^(h))—S(O)₂—R^(h), —N(R^(h))—S(O)—N(R^(h))₂, and —N(R^(h))—S(O)₂—N(R^(h))₂, wherein any C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, carbocyclyl, and heterocyclyl of the substituent groups is optionally substituted with one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, —NO₂, —N(R^(h))₂, —CN, —C(O)—N(R^(h))₂, —S(O)—N(R^(h))₂, —S(O)₂—N(R^(h))₂, —O—R^(h), —S—R^(h), —O—C(O)—R^(h), —C(O)—R^(h), —C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h), —C(O)—N(R^(h))₂, —N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)—R^(h), N(R^(h))—S(O)₂—R^(h), and C₁₋₆alkyl, which carbocyclyl and C₁₋₆alkyl are optionally substituted with one or more groups independently selected from oxo, halo, C₁₋₆alkyl, cyano, —O—R^(h), heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo and C₁₋₆alkyl.

In certain embodiments R^(c) is hydrogen, C₁₋₆alkyl, or C₃₋₈cycloalkyl, wherein each C₁₋₆alkyl and C₃₋₈cycloalkyl is optionally substituted with one or more substituent groups independently selected from —O—R^(h).

In certain embodiments R^(c) is hydrogen, methyl, ethyl, cyclopropyl, cyclobutyl, or 2-methoxyethyl.

In certain embodiments R^(c) is hydrogen.

In certain embodiments R^(c) is methyl, ethyl, cyclopropyl, cyclobutyl, or 2-methoxyethyl.

In certain embodiments R^(d) is C₁₋₆alkyl, carbocyclyl or heterocyclyl, wherein each C₁₋₆alkyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more substituent groups independently selected from oxo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, heterocyclyl, —F, —Cl, —Br, —I, —NO₂, —N(R^(v))₂, —CN, —C(O)—N(R^(h))₂, —S(O)—N(R^(h))₂, —S(O)₂—N(R^(h))₂, —O—R^(h), —S—R^(h), —O—C(O)—R^(h), —O—C(O)—O—R^(h), —C(O)—R^(h), —C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h), —O—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—OR^(h), —N(R^(h)) C(O)—N(R^(h))₂, —N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)—R^(h), —N(R^(h))—S(O)₂—R^(h), —N(R^(h))—S(O)—N(R^(h))₂, and —N(R^(h))—S(O)₂—N(R^(h))₂, wherein any C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl of the substituent groups is optionally substituted with one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, —NO₂, —N(R^(h))₂, —CN, —C(O)—N(R^(h))₂, —S(O)—N(R^(h))₂, —S(O)₂—N(R^(h))₂, —O—R^(h), —S—R^(h), —O—C(O)—R^(h), —C(O)—R^(h), —C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h), —C(O)—N(R^(h))₂, —N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)—R^(h), N(R^(h))—S(O)₂—R^(h), and C₁₋₆alkyl, which heterocyclyl, carbocyclyl and C₁₋₆alkyl are optionally substituted with one or more groups independently selected from oxo, halo, C₁₋₆alkyl, cyano, —O—R^(h), heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo and C₁₋₆alkyl.

In certain embodiments R^(d) is C₁₋₆alkyl, carbocyclyl or heterocyclyl, wherein each C₁₋₆alkyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more substituent groups independently selected from oxo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, heterocyclyl, —F, —Cl, —Br, —I, —NO₂, —N(R^(v))₂, —CN, —C(O)—N(R^(h))₂, —S(O)—N(R^(h))₂, —S(O)₂—N(R^(h))₂, —O—R^(h), —S—R^(h), —O—C(O)—R^(h), —O—C(O)—O—R^(h), —C(O)—R^(h), —C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h), —O—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—OR^(h), —N(R^(h))—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)—R^(h), —N(R^(h))—S(O)₂—R^(h), —N(R^(h))—S(O)—N(R^(h))₂, and —N(R^(h))—S(O)₂—N(R^(h))₂, wherein any C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, carbocyclyl, and heterocyclyl of the substituent groups is optionally substituted with one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, —NO₂, —N(R^(h)), —CN, —C(O)—N(R^(h))₂, —S(O)—N(R^(h))₂, —S(O)₂—N(R^(h))₂, —O—R^(h), —S—R^(h), —O—C(O)—R^(h), —C(O)—R^(h), —C(O)O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h), —C(O)—N(R^(h))₂, —N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)—R^(h), N(R^(h))—S(O)₂—R^(h), and C₁₋₆alkyl, which carbocyclyl and C₁₋₆alkyl are optionally substituted with one or more groups independently selected from oxo, halo, cyano, —O—R^(h), heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo and C₁₋₆alkyl.

In certain embodiments R^(d) is C₁₋₆alkyl that is optionally substituted with one or more substituent groups independently selected from oxo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, heterocyclyl, —F, —Cl, —Br, —I, —NO₂, —N(R^(v))₂, —CN, —C(O)—N(R^(h))₂, —S(O)—N(R^(h))₂, —S(O)₂—N(R^(h))₂, —O—R^(h), —S—R^(h), —O—C(O)—R^(h), —O—C(O)—O—R^(h), —C(O)—R^(h), —C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h), —O—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—OR^(h), —N(R^(h))—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)—R^(h), —N(R^(h))—S(O)₂—R^(h), —N(R^(h))—S(O)—N(R^(h))₂, and —N(R^(h))—S(O)₂—N(R^(h))₂, wherein any C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, and heterocyclyl of the substituent groups is optionally substituted with one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, —NO₂, —N(R^(h))₂, —CN, —C(O)—N(R^(h))₂, —S(O)—N(R^(h))₂, —S(O)₂—N(R^(h))₂, —O—R^(h), —S—R^(h), —O—C(O)—R^(h), —C(O)—R^(h), —C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h), —C(O)—N(R^(h))₂, —N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O) R^(h), N(R^(h))—S(O)₂—R^(h), and C₁₋₆alkyl, which heterocyclyl, carbocyclyl and C₁₋₆alkyl are optionally substituted with one or more groups independently selected from oxo, halo, C₁₋₆alkyl, cyano, —O—R^(h), heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo and C₁₋₆alkyl.

In certain embodiments R^(d) is C₁₋₆alkyl that is optionally substituted with one or more substituent groups independently selected from oxo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, heterocyclyl, —F, —Cl, —Br, —I, —NO₂, —N(R^(v))₂, —CN, —C(O)—N(R^(h))₂, —S(O)—N(R^(h))₂, —S(O)₂—N(R^(h))₂, —O—R^(h), —S—R^(h), —O—C(O)—R^(h), —O—C(O)—O—R^(h), —C(O)—R^(h), —C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h), —O—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—OR^(h), —N(R^(h))—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)—R^(h), —N(R^(h))—S(O)₂—R^(h), —N(R^(h))—S(O)—N(R^(h)), and —N(R^(h))—S(O)₂—N(R^(h))₂, wherein any C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, carbocyclyl, and heterocyclyl of the substituent groups is optionally substituted with one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, —NO₂, —N(R^(h))₂, —CN, —C(O)—N(R^(h))₂, —S(O)—N(R^(h))₂, —S(O)₂—N(R^(h))₂, —O—R^(h), —S—R^(h), —O—C(O)—R^(h), —C(O)—R^(h), —C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h), —C(O)—N(R^(h))₂, —N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)—R^(h), N(R^(h))—S(O)₂—R^(h), and C₁₋₆alkyl, which carbocyclyl and C₁₋₆alkyl are optionally substituted with one or more groups independently selected from oxo, halo, cyano, —O—R^(h), heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo and C₁₋₆alkyl.

In certain embodiments R^(d) is carbocyclyl that is optionally substituted with one or more substituent groups independently selected from oxo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, heterocyclyl, —F, —Cl, —Br, —I, —NO₂, —N(R^(v))₂, —CN, —C(O)—N(R^(h))₂, —S(O)—N(R^(h))₂, —S(O)₂—N(R^(h))₂, —O—R^(h), —S—R^(h), —O—C(O)R^(h), —O—C(O)—O—R^(h), —C(O)—R^(h), —C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h), —O—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—OR^(h), —N(R^(h))—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)—R^(h), —N(R^(h))—S(O)₂—R^(h), —N(R^(h))—S(O)—N(R^(h))₂, and —N(R^(h))—S(O)₂—N(R^(h))₂, wherein any C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl of the substituent groups is optionally substituted with one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, —NO₂, —N(R^(h))₂, —CN, —C(O)—N(R^(h))₂, —S(O)—N(R^(h))₂, —S(O)₂—N(R^(h))₂, —O—R^(h), —S—R^(h), —O—C(O)—R^(h), —C(O)—R^(h), —C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h), —C(O)—N(R^(h)), —N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)—R^(h), N(R^(h))—S(O)₂—R^(h), and C₁₋₆alkyl, which heterocyclyl, carbocyclyl and C₁₋₆alkyl are optionally substituted with one or more groups independently selected from oxo, halo, C₁₋₆alkyl, cyano, —O—R^(h), heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo and C₁₋₆alkyl.

In certain embodiments R^(d) is carbocyclyl that is optionally substituted with one or more substituent groups independently selected from oxo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, heterocyclyl, —F, —Cl, —Br, —I, —NO₂, —N(R^(v))₂, —CN, —C(O)—N(R^(h))₂, —S(O)—N(R^(h))₂, —S(O)₂—N(R^(h))₂, —O—R^(h), —S—R^(h), —O—C(O)—R^(h), —O—C(O)—O—R^(h), —C(O)—R^(h), —C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h), —O—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—OR^(h), —N(R^(h))—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)—R^(h), —N(R^(h))—S(O)₂—R^(h), —N(R^(h))—S(O)—N(R^(h))₂, and —N(R^(h))—S(O)₂—N(R^(h))₂, wherein any C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, carbocyclyl, and heterocyclyl of the substituent groups is optionally substituted with one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, —NO₂, —N(R^(h))₂, —CN, —C(O)—N(R^(h))₂, —S(O)—N(R^(h))₂, —S(O)₂—N(R^(h))₂, —O—R^(h), —S—R^(h), —O—C(O)—R^(h), —C(O)—R^(h), —C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h), —C(O)—N(R^(h))₂, —N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)—R^(h), N(R^(h))—S(O)₂—R^(h), and C₁₋₆alkyl, which carbocyclyl and C₁₋₆alkyl are optionally substituted with one or more groups independently selected from oxo, halo, C₁₋₆alkyl, cyano, —O—R^(h), heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo and C₁₋₆alkyl.

In certain embodiments R^(d) is heterocyclyl that is optionally substituted with one or more substituent groups independently selected from oxo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, heterocyclyl, —F, —Cl, —Br, —I, —NO₂, —N(R^(v))₂, —CN, —C(O)—N(R^(h))₂, —S(O)—N(R^(h))₂, —S(O)₂—N(R^(h))₂, —O—R^(h), —S—R^(h), —O—C(O)—R^(h), —O—C(O)—O—R^(h), —C(O)—R^(h), —C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h), —O—C(O)—N(R^(h))₂, —N(R^(h)) C(O)—OR^(h), —N(R^(h))—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)—R^(h), —N(R^(h))—S(O)₂—R^(h), —N(R^(h))—S(O)—N(R^(h))₂, and —N(R^(h))—S(O)₂—N(R^(h))₂, wherein any C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl of the substituent groups is optionally substituted with one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, —NO₂, —N(R^(h))₂, —CN, —C(O)—N(R^(h))₂, —S(O)—N(R^(h))₂, —S(O)₂—N(R^(h))₂, —O—R^(h), —S—R^(h), —O—C(O)—R^(h), —C(O)—R^(h), —C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h), —C(O)—N(R^(h))₂, —N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)—R^(h), N(R^(h))—S(O)₂—R^(h), and C₁₋₆alkyl, which heterocyclyl, carbocyclyl and C₁₋₆alkyl are optionally substituted with one or more groups independently selected from oxo, halo, C₁₋₆alkyl, cyano, —O—R^(h), heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo and C₁₋₆alkyl.

In certain embodiments R^(d) is heterocyclyl that is optionally substituted with one or more substituent groups independently selected from oxo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, heterocyclyl, —F, —Cl, —Br, —I, —NO₂, —N(R^(v))₂, —CN, —C(O)—N(R^(h))₂, —S(O)—N(R^(h))₂, —S(O)₂—N(R², —O—R^(h), —S—R^(h), —O—C(O)—R^(h), —O—C(O)—O—R^(h), —C(O)—R^(h), —C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h), —O—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—OR^(h), —N(R^(h))—C(O)—N(R^(h))₂, —N(R^(h))—C(O)R^(h), —N(R^(h)) S(O)—R^(h), —N(R^(h))—S(O)₂—R^(h), —N(R^(h))—S(O)—N(R^(h))₂, and —N(R^(h))—S(O)₂—N(R^(h))₂, wherein any C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, carbocyclyl, and heterocyclyl of the substituent groups is optionally substituted with one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, —NO₂, —N(R^(h))₂, —CN, —C(O)—N(R^(h))₂, —S(O)—N(R^(h))₂, —S(O)₂—N(R^(h)), —O—R^(h), —S—R^(h), —O—C(O)—R^(h), —C(O)—R^(h), —C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h), —C(O)—N(R^(h))₂, —N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)—R^(h), N(R^(h))—S(O)₂—R^(h), and C₁₋₆alkyl, which carbocyclyl and C₁₋₆alkyl are optionally substituted with one or more groups independently selected from oxo, halo, C₁₋₆alkyl, cyano, —O—R^(h), heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo and C₁₋₆alkyl.

In certain embodiments R^(c) and R^(d) are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, heterocyclyl, —F, —Cl, —Br, —I, —NO₂, —N(R^(v))₂, —CN, —C(O)—N(R^(h))₂, —S(O)—N(R^(h))₂, —S(O)₂—N(R^(h))₂, —O—R^(h), —S—R^(h), —O—C(O)—R^(h), —O—C(O)—O—R^(h), —C(O)—R^(h), —C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h), —O—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—OR^(h), —N(R^(h))—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)—R^(h), —N(R^(h))—S(O)₂—R^(h), —N(R^(h))—S(O)—N(R^(h))₂, and —N(R^(h))—S(O)₂—N(R^(h))₂, wherein any C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from C₁₋₆alkyl, carbocyclyl, heterocyclyl, —F, —Cl, —Br, —I, —NO₂, —N(R^(h))₂, —CN, —C(O)—N(R^(h))₂, —S(O)—N(R^(h))₂, —S(O)₂—N(R^(h))₂, —O—R^(h), —S—R^(h), —O—C(O)—R^(h), —O—C(O)—O—R^(h), —C(O)—R^(h), —C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h), —O—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—R^(h), —N(R^(h))—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)—R^(h), —N(R^(h))—S(O)₂—R^(h), —N(R^(h))—S(O)—N(R^(h))₂, and —N(R^(h))—S(O)₂—N(R^(h))₂, which C₁₋₆alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more groups independently selected from halo and C₁₋₆alkyl.

In certain embodiments R^(c) and R^(d) are taken together with the nitrogen to which they are attached to form a 5-6 membered monocyclic heterocyclyl or a 8-12 membered bicyclic heterocyclyl, wherein the monocyclic or bicyclic heterocyclyl is optionally substituted with one or more groups independently selected from oxo, C₁₋₆₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, heterocyclyl, —F, —Cl, —Br, —I, —NO₂, —N(R^(v))₂, —CN, —C(O)—N(R^(h))₂, —S(O)—N(R^(h))₂, —S(O)₂—N(R^(h))₂, —O—R^(h), —S—R^(h), —O—C(O)—R^(h), —O—C(O)—O—R^(h), —C(O)—R^(h), —C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h), —O—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—OR^(h), —N(R^(h))—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)—R^(h), —N(R^(h))—S(O)₂—R^(h), —N(R^(h))—S(O)—N(R^(h))₂, and —N(R^(h))—S(O)₂—N(R^(h))₂, wherein any C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from C₁₋₆alkyl, carbocyclyl, heterocyclyl, —F, —Cl, —Br, —I, —NO₂, —N(R^(h))₂, —CN, —C(O)—N(R^(h))₂, —S(O)—N(R^(h))₂, —S(O)₂—N(R^(h))₂, —O—R^(h), —S—R^(h), —O—C(O)—R^(h), —O—C(O)—O—R^(h), —C(O)—R^(h), —C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h), —O—C(O)—N(R^(h)), —N(R^(h))—C(O)—OR^(h), —N(R^(h))—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)—R^(h), —N(R^(h))—S(O)₂—R^(h), —N(R^(h))—S(O)—N(R^(h))₂, and —N(R^(h))—S(O)₂—N(R^(h))₂, which C₁₋₆alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more groups independently selected from halo and C₁₋₆alkyl.

In certain embodiments the compound is a compound as described in the Examples herein, or a freebase or salt thereof.

In certain embodiments —C(═O)NR^(c)R^(d) is selected from:

In certain embodiments —C(═O)NR^(c)R^(d) is selected from:

In certain embodiments the compound is selected from:

and salts thereof.

In certain embodiments the compound is selected from:

and salts thereof.

In certain embodiments the invention provides compound 1000 as described in Examples 292 and 294, and salts thereof. The invention also provides a method for evaluating a compound's ability to inhibit TAF1-BD2 by monitoring the engagement of compound 1000 with a TAF1-BD2 target as described in Example 265.

In certain embodiments the invention provides compound 1001 as described in Examples 293 and 294, and salts thereof. The invention also provides a method for evaluating a compound's ability to inhibit CECR2 by monitoring the engagement of compound 1001 with a CECR2 target as described in Example 265

Uses, Formulation and Administration

Pharmaceutically Acceptable Compositions

Another aspect includes a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof. In one embodiment, the composition further comprises a pharmaceutically acceptable carrier, adjuvant, or vehicle. In another embodiment, the composition further comprises an amount of the compound effective to measurably inhibit a bromodomain. In certain embodiments, the composition is formulated for administration to a patient in need thereof.

The term “patient” or “individual” as used herein, refers to an animal, such as a mammal, such as a human. In one embodiment, patient or individual refers to a human.

The term “pharmaceutically acceptable carrier, adjuvant, or vehicle” refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

Compositions comprising a compound of formula I or salt thereof may be administered orally, parenterally, by inhalation spray, topically, transdermally, rectally, nasally, buccally, sublingually, vaginally, intraperitoneal, intrapulmonary, intradermal, epidural or via an implanted reservoir. The term “parenteral” as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.

In one embodiment, the composition comprising a compound of formula I or salt thereof is formulated as a solid dosage form for oral administration. Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In certain embodiments, the solid oral dosage form comprising a compound of formula (I) or a salt thereof further comprises one or more of (i) an inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and (ii) filler or extender such as starches, lactose, sucrose, glucose, mannitol, or silicic acid, (iii) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose or acacia, (iv) humectants such as glycerol, (v) disintegrating agent such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates or sodium carbonate, (vi) solution retarding agents such as paraffin, (vii) absorption accelerators such as quaternary ammonium salts, (viii) a wetting agent such as cetyl alcohol or glycerol monostearate, (ix) absorbent such as kaolin or bentonite clay, and (x) lubricant such as talc, calcium stearate, magnesium stearate, polyethylene glycols or sodium lauryl sulfate. In certain embodiments, the solid oral dosage form is formulated as capsules, tablets or pills. In certain embodiments, the solid oral dosage form further comprises buffering agents. In certain embodiments, such compositions for solid oral dosage forms may be formulated as fillers in soft and hard-filled gelatin capsules comprising one or more excipients such as lactose or milk sugar, polyethylene glycols and the like.

In certain embodiments, tablets, dragees, capsules, pills and granules of the compositions comprising a compound of formula I or salt thereof optionally comprise coatings or shells such as enteric coatings. They may optionally comprise opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions include polymeric substances and waxes, which may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.

In another embodiment, a composition comprises micro-encapsulated compound of formula (I) or salt thereof, and optionally, further comprises one or more excipients.

In another embodiment, compositions comprise liquid dosage formulations comprising a compound of formula I or salt thereof for oral administration, and optionally further comprise one or more of pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In certain embodiments, the liquid dosage form optionally, further comprise one or more of an inert diluent such as water or other solvent, a solubilizing agent, and an emulsifier such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols or fatty acid esters of sorbitan, and mixtures thereof. In certain embodiments, liquid oral compositions optionally further comprise one or more adjuvant, such as a wetting agent, a suspending agent, a sweetening agent, a flavoring agent and a perfuming agent.

Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

In order to prolong the effect of a compound of formula (I), it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

In certain embodiments, the composition for rectal or vaginal administration are formulated as suppositories which can be prepared by mixing a compound of formula (I) or a salt thereof with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax, for example those which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the compound of formula (I).

Example dosage forms for topical or transdermal administration of a compound of formula (I) include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The compound of formula (I) or a salt thereof is admixed under sterile conditions with a pharmaceutically acceptable carrier, and optionally preservatives or buffers. Additional formulation examples include an ophthalmic formulation, ear drops, eye drops, transdermal patches. Transdermal dosage forms can be made by dissolving or dispensing the compound of formula (I) or a salt thereof in medium, for example ethanol or dimethylsulfoxide. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

Nasal aerosol or inhalation formulations of a compound of formula (I) or a salt thereof may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.

In certain embodiments, pharmaceutical compositions may be administered with or without food. In certain embodiments, pharmaceutically acceptable compositions are administered without food. In certain embodiments, pharmaceutically acceptable compositions of this invention are administered with food.

Specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the judgment of the treating physician, and the severity of the particular disease being treated. The amount of a provided compound of formula i or salt thereof in the composition will also depend upon the particular compound in the composition.

In one embodiment, the therapeutically effective amount of the compound of the invention administered parenterally per dose will be in the range of about 0.01-100 mg/kg, alternatively about 0.1 to 20 mg/kg of patient body weight per day, with the typical initial range of compound used being 0.3 to 15 mg/kg/day. In another embodiment, oral unit dosage forms, such as tablets and capsules, contain from about 5 to about 100 mg of the compound of the invention.

An example tablet oral dosage form comprises about 2 mg, 5 mg, 25 mg, 50 mg, 100 mg, 250 mg or 500 mg of a compound of formula (I) or salt thereof, and further comprises about 5-30 mg anhydrous lactose, about 5-40 mg sodium croscarmellose, about 5-30 mg polyvinylpyrrolidone (PVP) K30 and about 1-10 mg magnesium stearate. The process of formulating the tablet comprises mixing the powdered ingredients together and further mixing with a solution of the PVP. The resulting composition can be dried, granulated, mixed with the magnesium stearate and compressed to tablet form using conventional equipment. An example of an aerosol formulation can be prepared by dissolving about 2-500 mg of a compound of formula I or salt thereof, in a suitable buffer solution, e.g. a phosphate buffer, and adding a tonicifier, e.g. a salt such sodium chloride, if desired. The solution may be filtered, e.g. using a 0.2 micron filter, to remove impurities and contaminants.

Uses of Compounds and Pharmaceutically Acceptable Compositions

Another aspect includes the use of a compound of formula (I) or a salt thereof for the inhibition of a bromodomain (in vitro or in vivo).

Another embodiment includes a method for treating a bromodomain-mediated disorder in an animal comprising administering a compound of formula (I), or a pharmaceutically acceptable salt thereof to the animal. Bromodomain-mediated disorders include, but are not limited to those disorders described herein.

Another embodiment includes a method of increasing efficacy of a cancer treatment comprising a cytotoxic agent in an animal comprising administering to the animal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

Another embodiment includes a method of delaying or preventing development of cancer resistance to a cytotoxic agent in an animal, comprising administering to the animal a compound of formula (I) or a pharmaceutically acceptable salt thereof.

Another embodiment includes a method of extending the duration of response to a cancer therapy in an animal, comprising administering to an animal undergoing the cancer therapy a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the duration of response to the cancer therapy when the compound of formula (I) or the pharmaceutically acceptable salt thereof is administered is extended over the duration of response to the cancer therapy in the absence of the administration of the compound of formula (I) or the pharmaceutically acceptable salt thereof.

Another embodiment includes a method of treating cancer in an individual comprising administering to the individual (a) a compound of formula (I) or a pharmaceutically acceptable salt thereof, and (b) a cytotoxic agent. In one embodiment the cytotoxic agent is selected from anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormonal analogues, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents, proapoptotic agents, inhibitors of LDH-A, inhibitors of fatty acid biosynthesis, cell cycle signaling inhibitors, HDAC inhibitors, proteasome inhibitors, and inhibitors of cancer metabolism. In one embodiment the cytotoxic agent is a taxane. In one embodiment the taxane is paclitaxel or docetaxel. In one embodiment the cytotoxic agent is a platinum agent. In one embodiment the cytotoxic agent is an antagonist of EGFR. In one embodiment the antagonist of EGFR is N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine or a pharmaceutically acceptable salt thereof (e.g., erlotinib). In one embodiment the cytotoxic agent is a RAF inhibitor. In one embodiment the RAF inhibitor is a BRAF or CRAF inhibitor. In one embodiment the RAF inhibitor is vemurafenib. In one embodiment the cytotoxic agent is a PI3K inhibitor.

In certain embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.

Bromodomain-Mediated Disorders

A “bromodomain-mediated disorder” is characterized by the participation of one or more bromodomains (e.g., BRD4) in the inception, manifestation of one or more symptoms or disease markers, severity, or progression of a disorder. Bromodomains include, but are not limited to ASH1L, ATAD2, ATAD2B, BAZ1A, BAZ1B, BAZ2A, BAZ2B, BPTF, BRD1, BRD2, BRD3, BRD4, BRD7, BRD8, BRD9, BRDT, BRPF1, BRPF3, BRWD1, BRWD3, CECR2, CREBBP (aka, CBP), EP300, GCN5L2, KIAA2026, MLL, MLL4, PBRM, PCAF, PHIP, SMARCA2, SMARCA4, SP100, SP110, SP140, SP140L, TAF1, TAF1L, TRIM24, TRIM28, TRIM33, TRIM66, ZMYND8, and ZMYND11.

Bromodomain-mediated disorders include cancers, including, but not limited to acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic (granulocytic) leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferative changes (dysplasias and metaplasias), embryonal carcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen-receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, hepatoma, hepatocellular cancer, hormone insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's and non-Hodgkin's), malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovaries, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid tumors (carcinomas and sarcomas), small cell lung cancer, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, Waldenstr6m's macroglobulinemia, testicular tumors, uterine cancer and Wilms' tumor.

In certain embodiments, the cancer is lung cancer, breast cancer, pancreatic cancer, colorectal cancer, and/or melanoma. In certain embodiments, the cancer is lung. In certain embodiments, the lung cancer is NSCLC. In certain embodiments, the cancer is breast cancer. In certain embodiments, the cancer is melanoma.

Bromodomain-mediated disorders also include inflammatory diseases, inflammatory conditions, and autoimmune diseases, including, but not limited to: Addison's disease, acute gout, ankylosing spondylitis, asthma, atherosclerosis, Beheet's disease, bullous skin diseases, chronic obstructive pulmonary disease (COPD), Crohn's disease, dermatitis, eczema, giant cell arteritis, glomerulonephritis, hepatitis, hypophysitis, inflammatory bowel disease, Kawasaki disease, lupus nephritis, multiple sclerosis, myocarditis, myositis, nephritis, organ transplant rejection, osteoarthritis, pancreatitis, pericarditis, Polyarteritis nodosa, pneumonitis, primary biliary cirrhosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, scleritis, sclerosing cholangitis, sepsis, systemic lupus erythematosus, Takayasu's Arteritis, toxic shock, thyroiditis, type I diabetes, ulcerative colitis, uveitis, vitiligo, vasculitis, and Wegener's granulomatosis.

Bromodomain-mediated disorders also include AIDS; chronic kidney diseases, including, but are not limited to diabetic nephropathy, hypertensive nephropathy, HIV-associated nephropathy, glomerulonephritis, lupus nephritis, IgA nephropathy, focal segmental glomerulosclerosis, membranous glomerulonephritis, minimal change disease, polycystic kidney disease and tubular interstitial nephritis; acute kidney injury or disease or condition including, but are not limited to ischemia-reperfusion induced, cardiac and major surgery induced, percutaneous coronary intervention induced, radio-contrast agent induced, sepsis induced, pneumonia induced, and drug toxicity induced; obesity; dyslipidemia; hypercholesterolemia; Alzheimer's disease; metabolic syndrome; hepatic steatosis; type II diabetes; insulin resistance; and diabetic retinopathy.

Bromodomain inhibitors may also be used to provide male contraception.

Co-Administration of Compounds and Other Agents

The compounds of formula (I) or salts thereof may be employed alone or in combination with other agents for treatment. For example, the second agent of the pharmaceutical combination formulation or dosing regimen may have complementary activities to the compound of formula (I) such that they do not adversely affect each other. The compounds may be administered together in a unitary pharmaceutical composition or separately. In one embodiment a compound or a pharmaceutically acceptable salt can be co-administered with a cytotoxic agent to treat proliferative diseases and cancer.

The term “co-administering” refers to either simultaneous administration, or any manner of separate sequential administration, of a compound of formula (I) or a salt thereof, and a further active pharmaceutical ingredient or ingredients, including cytotoxic agents and radiation treatment. If the administration is not simultaneous, the compounds are administered in a close time proximity to each other. Furthermore, it does not matter if the compounds are administered in the same dosage form, e.g. one compound may be administered topically and another compound may be administered orally.

Typically, any agent that has activity against a disease or condition being treated may be co-administered. Examples of such agents can be found in Cancer Principles and Practice of Oncology by V. T. Devita and S. Hellman (editors), 6^(th) edition (Feb. 15, 2001), Lippincott Williams & Wilkins Publishers. A person of ordinary skill in the art would be able to discern which combinations of agents would be useful based on the particular characteristics of the drugs and the disease involved.

In one embodiment, the treatment method includes the co-administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one cytotoxic agent. The term “cytotoxic agent” as used herein refers to a substance that inhibits or prevents a cellular function and/or causes cell death or destruction. Cytotoxic agents include, but are not limited to, radioactive isotopes (e.g., At²¹¹, I¹³¹, I¹²⁵, Y⁹⁰, Re¹⁸⁶, Re¹⁸⁸, Sm¹⁵³, Bi²¹², P³², P^(b212) and radioactive isotopes of Lu); chemotherapeutic agents; growth inhibitory agents; enzymes and fragments thereof such as nucleolytic enzymes; and toxins such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, including fragments and/or variants thereof.

Exemplary cytotoxic agents can be selected from anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormonal analogues, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents, proapoptotic agents, inhibitors of LDH-A; inhibitors of fatty acid biosynthesis; cell cycle signaling inhibitors; HDAC inhibitors, proteasome inhibitors; and inhibitors of cancer metabolism.

“Chemotherapeutic agent” includes chemical compounds useful in the treatment of cancer. Examples of chemotherapeutic agents include erlotinib (TARCEVA®, Genentech/OSI Pharm.), bortezomib (VELCADE®, Millennium Pharm.), disulfiram, epigallocatechin gallate, salinosporamide A, carfilzomib, 17-AAG(geldanamycin), radicicol, lactate dehydrogenase A (LDH-A), fulvestrant (FASLODEX®, AstraZeneca), sunitib (SUTENT®, Pfizer/Sugen), letrozole (FEMARA®, Novartis), imatinib mesylate (GLEEVEC®, Novartis), finasunate (VATALANIB®, Novartis), oxaliplatin (ELOXATIN®, Sanofi), 5-FU (5-fluorouracil), leucovorin, Rapamycin (Sirolimus, RAPAMUNE®, Wyeth), Lapatinib (TYKERB®, GSK572016, Glaxo Smith Kline), Lonafamib (SCH 66336), sorafenib (NEXAVAR®, Bayer Labs), gefitinib (IRESSA®, AstraZeneca), AG1478, alkylating agents such as thiotepa and CYTOXAN® cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including topotecan and irinotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogs); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); adrenocorticosteroids (including prednisone and prednisolone); cyproterone acetate; 5α-reductases including finasteride and dutasteride); vorinostat, romidepsin, panobinostat, valproic acid, mocetinostat dolastatin; aldesleukin, talc duocarmycin (including the synthetic analogs, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlomaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin γ1I and calicheamicin ω1I (Angew Chem. Intl. Ed Engl. 1994 33:183-186); dynemicin, including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN® (doxorubicin), morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid, eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfomithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidamnol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin; sizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2′,2″-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxoids, e.g., TAXOL (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, N.J.), ABRAXANE® (Cremophor-free), albumin-engineered nanoparticle formulations of paclitaxel (American Pharmaceutical Partners, Schaumberg, Ill.), and TAXOTERE® (docetaxel, doxetaxel; Sanofi-Aventis); chloranmbucil; GEMZAR® (gemcitabine); 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; NAVELBINE® (vinorelbine); novantrone; teniposide; edatrexate; daunomycin; aminopterin; capecitabine (XELODA®); ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; and pharmaceutically acceptable salts, acids and derivatives of any of the above.

Chemotherapeutic agent also includes (i) anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti-estrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including NOLVADEX®; tamoxifen citrate), raloxifene, droloxifene, iodoxyfene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and FARESTON® (toremifine citrate); (ii) aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as, for example, 4(5)-imidazoles, aminoglutethimide, MEGASE® (megestrol acetate), AROMASIN® (exemestane; Pfizer), formestanie, fadrozole, RIVISOR® (vorozole), FEMARA® (letrozole; Novartis), and ARIMIDEX® (anastrozole; AstraZeneca); (iii) anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide and goserelin; buserelin, tripterelin, medroxyprogesterone acetate, diethylstilbestrol, premarin, fluoxymesterone, all transretionic acid, fenretinide, as well as troxacitabine (a 1,3-dioxolane nucleoside cytosine analog); (iv) protein kinase inhibitors; (v) lipid kinase inhibitors; (vi) antisense oligonucleotides, particularly those which inhibit expression of genes in signaling pathways implicated in aberrant cell proliferation, such as, for example, PKC-alpha, Ralf and H-Ras; (vii) ribozymes such as VEGF expression inhibitors (e.g., ANGIOZYME®) and HER2 expression inhibitors; (viii) vaccines such as gene therapy vaccines, for example, ALLOVECTIN®, LEUVECTIN®, and VAXID®; PROLEUKIN®, rIL-2; a topoisomerase 1 inhibitor such as LURTOTECAN®; ABARELIX® rmRH; and (ix) pharmaceutically acceptable salts, acids and derivatives of any of the above.

Chemotherapeutic agent also includes antibodies such as alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech); cetuximab (ERBITUX®, Imclone); panitumumab (VECTIBIX®, Amgen), rituximab (RITUXAN®, Genentech/Biogen Idec), pertuzumab (OMNITARG®, 2C4, Genentech), trastuzumab (HERCEPTIN®, Genentech), tositumomab (Bexxar, Corixia), and the antibody drug conjugate, gemtuzumab ozogamicin (MYLOTARG®, Wyeth). Additional humanized monoclonal antibodies with therapeutic potential as agents in combination with the compounds of the invention include: apolizumab, aselizumab, atlizumab, bapineuzumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, certolizumab pegol, cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, motovizumab, natalizumab, nimotuzumab, nolovizumab, numavizumab, ocrelizumab, omalizumab, palivizumab, pascolizumab, pecfusituzumab, pectuzumab, pexelizumab, ralivizumab, ranibizumab, reslivizumab, reslizumab, resyvizumab, rovelizumab, ruplizumab, sibrotuzumab, siplizumab, sontuzumab, tacatuzumab tetraxetan, tadocizumab, talizumab, tefibazumab, tocilizumab, toralizumab, tucotuzumab celmoleukin, tucusituzumab, umavizumab, urtoxazumab, ustekinumab, visilizumab, and the anti-interleukin-12 (ABT-874/J695, Wyeth Research and Abbott Laboratories) which is a recombinant exclusively human-sequence, full-length IgG₁λ antibody genetically modified to recognize interleukin-12 p40 protein.

Chemotherapeutic agent also includes “EGFR inhibitors,” which refers to compounds that bind to or otherwise interact directly with EGFR and prevent or reduce its signaling activity, and is alternatively referred to as an “EGFR antagonist.” Examples of such agents include antibodies and small molecules that bind to EGFR. Examples of antibodies which bind to EGFR include MAb 579 (ATCC CRL HB 8506), MAb 455 (ATCC CRL HB8507), MAb 225 (ATCC CRL 8508), MAb 528 (ATCC CRL 8509) (see, U.S. Pat. No. 4,943,533, Mendelsohn et al.) and variants thereof, such as chimerized 225 (C225 or Cetuximab; ERBUTIX®) and reshaped human 225 (H225) (see, WO 96/40210, Imclone Systems Inc.); IMC-11F8, a fully human, EGFR-targeted antibody (Imclone); antibodies that bind type II mutant EGFR (U.S. Pat. No. 5,212,290); humanized and chimeric antibodies that bind EGFR as described in U.S. Pat. No. 5,891,996; and human antibodies that bind EGFR, such as ABX-EGF or Panitumumab (see WO98/50433, Abgenix/Amgen); EMD 55900 (Stragliotto et al. Eur. J. Cancer 32A:636-640 (1996)); EMD7200 (matuzumab) a humanized EGFR antibody directed against EGFR that competes with both EGF and TGF-alpha for EGFR binding (EMD/Merck); human EGFR antibody, HuMax-EGFR (GenMab); fully human antibodies known as E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 and E7.6.3 and described in U.S. Pat. No. 6,235,883; MDX-447 (Medarex Inc); and mAb 806 or humanized mAb 806 (Johns et al., J. Biol. Chem. 279(29):30375-30384 (2004)). The anti-EGFR antibody may be conjugated with a cytotoxic agent, thus generating an immunoconjugate (see, e.g., EP659,439A2, Merck Patent GmbH). EGFR antagonists include small molecules such as compounds described in U.S. Pat. Nos. 5,616,582, 5,457,105, 5,475,001, 5,654,307, 5,679,683, 6,084,095, 6,265,410, 6,455,534, 6,521,620, 6,596,726, 6,713,484, 5,770,599, 6,140,332, 5,866,572, 6,399,602, 6,344,459, 6,602,863, 6,391,874, 6,344,455, 5,760,041, 6,002,008, and 5,747,498, as well as the following PCT publications: WO98/14451, WO98/50038, WO99/09016, and WO99/24037. Particular small molecule EGFR antagonists include OSI-774 (CP-358774, erlotinib, TARCEVA® Genentech/OSI Pharmaceuticals); PD 183805 (CI 1033, 2-propenamide, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(4-morpholinyl)propoxy]-6-quinazolinyl]-, dihydrochloride, Pfizer Inc.); ZD1839, gefitinib (IRESSA®) 4-(3′-Chloro-4′-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline, AstraZeneca); ZM 105180 ((6-amino-4-(3-methylphenyl-amino)-quinazoline, Zeneca); BIBX-1382 (N8-(3-chloro-4-fluoro-phenyl)-N2-(1-methylpiperidin-4-yl)-pyrimido[5,4-d]pyrimidine-2,8-diamine, Boehringer Ingelheim); PKI-166 ((R)-4-[4-[(1-phenylethyl)amino]-1H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenol); (R)-6-(4-hydroxyphenyl)-4-[(1-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine); CL-387785 (N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-2-butynamide); EKB-569 (N-[4-[(3-chloro-4-fluorophenyl)amino]-3-cyano-7-ethoxy-6-quinolinyl]-4-(dimethylamino)-2-butenamide) (Wyeth); AG1478 (Pfizer); AG1571 (SU 5271; Pfizer); dual EGFR/HER2 tyrosine kinase inhibitors such as lapatinib (TYKERB®, GSK572016 or N-[3-chloro-4-[(3 fluorophenyl)methoxy]phenyl]-6 [5 [[[2methylsulfonyl)ethyl]amino]methyl]-2-furanyl]-4-quinazolinamine).

Chemotherapeutic agents also include “tyrosine kinase inhibitors” including the EGFR-targeted drugs noted in the preceding paragraph; small molecule HER2 tyrosine kinase inhibitor such as TAK165 available from Takeda; CP-724,714, an oral selective inhibitor of the ErbB2 receptor tyrosine kinase (Pfizer and OSI); dual-HER inhibitors such as EKB-569 (available from Wyeth) which preferentially binds EGFR but inhibits both HER2 and EGFR-overexpressing cells; lapatinib (GSK572016; available from Glaxo-SmithKline), an oral HER2 and EGFR tyrosine kinase inhibitor, PKI-166 (available from Novartis); pan-HER inhibitors such as canertinib (CI-1033; Pharmacia); Raf-1 inhibitors such as antisense agent ISIS-5132 available from ISIS Pharmaceuticals which inhibit Raf-1 signaling; non-HER targeted TK inhibitors such as imatinib mesylate (GLEEVEC®, available from Glaxo SmithKline); multi-targeted tyrosine kinase inhibitors such as sunitinib (SUTENT®, available from Pfizer); VEGF receptor tyrosine kinase inhibitors such as vatalanib (PTK787/ZK222584, available from Novartis/Schering AG); MAPK extracellular regulated kinase I inhibitor CI-1040 (available from Pharmacia); quinazolines, such as PD 153035,4-(3-chloroanilino) quinazoline; pyridopyrimidines; pyrimidopyrimidines; pyrrolopyrimidines, such as CGP 59326, CGP 60261 and CGP 62706; pyrazolopyrimidines, 4-(phenylamino)-7H-pyrrolo[2,3-d] pyrimidines; curcumin (diferuloyl methane, 4,5-bis (4-fluoroanilino)phthalimide); tyrphostines containing nitrothiophene moieties; PD-0183805 (Warner-Lamber); antisense molecules (e.g. those that bind to HER-encoding nucleic acid); quinoxalines (U.S. Pat. No. 5,804,396); tryphostins (U.S. Pat. No. 5,804,396); ZD6474 (Astra Zeneca); PTK-787 (Novartis/Schering AG); pan-HER inhibitors such as CI-1033 (Pfizer); Affinitac (ISIS 3521; Isis/Lilly); imatinib mesylate (GLEEVECO); PKI 166 (Novartis); GW2016 (Glaxo SmithKline); CI-1033 (Pfizer); EKB-569 (Wyeth); Semaxinib (Pfizer); ZD6474 (AstraZeneca); PTK-787 (Novartis/Schering AG); INC-1C11 (Imclone), rapamycin (sirolimus, RAPAMUNE®); or as described in any of the following patent publications: U.S. Pat. No. 5,804,396; WO 1999/09016 (American Cyanamid); WO 1998/43960 (American Cyanamid); WO 1997/38983 (Warner Lambert); WO 1999/06378 (Warner Lambert); WO 1999/06396 (Warner Lambert); WO 1996/30347 (Pfizer, Inc); WO 1996/33978 (Zeneca); WO 1996/3397 (Zeneca) and WO 1996/33980 (Zeneca).

Chemotherapeutic agents also include dexamethasone, interferons, colchicine, metoprine, cyclosporine, amphotericin, metronidazole, alemtuzumab, alitretinoin, allopurinol, amifostine, arsenic trioxide, asparaginase, BCG live, bevacuzimab, bexarotene, cladribine, clofarabine, darbepoetin alfa, denileukin, dexrazoxane, epoetin alfa, elotinib, filgrastim, histrelin acetate, ibritumomab, interferon alfa-2a, interferon alfa-2b, lenalidomide, levamisole, mesna, methoxsalen, nandrolone, nelarabine, nofetumomab, oprelvekin, palifermin, pamidronate, pegademase, pegaspargase, pegfilgrastim, pemetrexed disodium, plicamycin, porfimer sodium, quinacrine, rasburicase, sargramostim, temozolomide, VM-26, 6-TG, toremifene, tretinoin, ATRA, valrubicin, zoledronate, and zoledronic acid, and pharmaceutically acceptable salts thereof.

Chemotherapeutic agents also include hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivalate, triamcinolone acetonide, triamcinolone alcohol, mometasone, amcinonide, budesonide, desonide, fluocinonide, fluocinolone acetonide, betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, fluocortolone, hydrocortisone-17-butyrate, hydrocortisone-17-valerate, aclometasone dipropionate, betamethasone valerate, betamethasone dipropionate, prednicarbate, clobetasone-17-butyrate, clobetasol-17-propionate, fluocortolone caproate, fluocortolone pivalate and fluprednidene acetate; immune selective anti-inflammatory peptides (ImSAIDs) such as phenylalanine-glutamine-glycine (FEG) and its D-isomeric form (feG) (IMULAN BioTherapeutics, LLC); anti-rheumatic drugs such as azathioprine, ciclosporin (cyclosporine A), D-penicillamine, gold salts, hydroxychloroquine, leflunomideminocycline, sulfasalazine, tumor necrosis factor alpha (TNFα) blockers such as etanercept (Enbrel), infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia), golimumab (Simponi), Interleukin 1 (IL-1) blockers such as anakinra (Kineret), T cell costimulation blockers such as abatacept (Orencia), Interleukin 6 (IL-6) blockers such as tocilizumab (ACTEMERA®); Interleukin 13 (IL-13) blockers such as lebrikizumab; Interferon alpha (IFN) blockers such as Rontalizumab; Beta 7 integrin blockers such as rhuMAb Beta7; IgE pathway blockers such as Anti-Mi prime; Secreted homotrimeric LTa3 and membrane bound heterotrimer LTa1/β2 blockers such as Anti-lymphotoxin alpha (LTa); radioactive isotopes (e.g., At²¹¹, I¹³¹, I¹²⁵, Y⁹⁰, Re¹⁸⁶, Re¹⁸⁸, Sm¹⁵³, Bi²¹², P³², Pb²¹² and radioactive isotopes of Lu); miscellaneous investigational agents such as thioplatin, PS-341, phenylbutyrate, ET-18-OCH₃, or farnesyl transferase inhibitors (L-739749, L-744832); polyphenols such as quercetin, resveratrol, piceatannol, epigallocatechine gallate, theaflavins, flavanols, procyanidins, betulinic acid and derivatives thereof; autophagy inhibitors such as chloroquine; delta-9-tetrahydrocannabinol (dronabinol, MARINOL®); beta-lapachone; lapachol; colchicines; betulinic acid; acetylcamptothecin, scopolectin, and 9-aminocamptothecin); podophyllotoxin; tegafur (UFTORAL®); bexarotene (TARGRETIN®); bisphosphonates such as clodronate (for example, BONEFOS® or OSTAC®), etidronate (DIDROCAL®), NE-58095, zoledronic acid/zoledronate (ZOMETA®), alendronate (FOSAMAX®), pamidronate (AREDIA®), tiludronate (SKELID®), or risedronate (ACTONEL®); and epidermal growth factor receptor (EGF-R); vaccines such as THERATOPE® vaccine; perifosine, COX-2 inhibitor (e.g. celecoxib or etoricoxib), proteosome inhibitor (e.g. PS341); CCI-779; tipifamib (R11577); orafenib, ABT510; Bcl-2 inhibitor such as oblimersen sodium (GENASENSE®); pixantrone; famesyltransferase inhibitors such as lonafarnib (SCH 6636, SARASAR™); and pharmaceutically acceptable salts, acids or derivatives of any of the above; as well as combinations of two or more of the above such as CHOP, an abbreviation for a combined therapy of cyclophosphamide, doxorubicin, vincristine, and prednisolone; and FOLFOX, an abbreviation for a treatment regimen with oxaliplatin (ELOXATIN™) combined with 5-FU and leucovorin.

Chemotherapeutic agents also include non-steroidal anti-inflammatory drugs with analgesic, antipyretic and anti-inflammatory effects. NSAIDs include non-selective inhibitors of the enzyme cyclooxygenase. Specific examples of NSAIDs include aspirin, propionic acid derivatives such as ibuprofen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin and naproxen, acetic acid derivatives such as indomethacin, sulindac, etodolac, diclofenac, enolic acid derivatives such as piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam and isoxicam, fenamic acid derivatives such as mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, and COX-2 inhibitors such as celecoxib, etoricoxib, lumiracoxib, parecoxib, rofecoxib, rofecoxib, and valdecoxib. NSAIDs can be indicated for the symptomatic relief of conditions such as rheumatoid arthritis, osteoarthritis, inflammatory arthropathies, ankylosing spondylitis, psoriatic arthritis, Reiter's syndrome, acute gout, dysmenorrhoea, metastatic bone pain, headache and migraine, postoperative pain, mild-to-moderate pain due to inflammation and tissue injury, pyrexia, ileus, and renal colic.

Chemotherapeutic agents also include treatments for Alzheimer's Disease such as donepezil hydrochloride and rivastigmine; treatments for Parkinson's Disease such as L-DOPA/carbidopa, entacapone, ropinrole, pramipexole, bromocriptine, pergolide, trihexephendyl, and amantadine; agents for treating multiple sclerosis (MS) such as beta interferon (e.g., Avonexo® and Rebif®), glatiramer acetate, and mitoxantrone; treatments for asthma such as albuterol and montelukast sodium; agents for treating schizophrenia such as zyprexa, risperdal, seroquel, and haloperidol; anti-inflammatory agents such as corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulatory and immunosuppressive agents such as cyclosporin, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophophamide, azathioprine, and sulfasalazine; neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anti-convulsants, ion channel blockers, riluzole, and anti-Parkinsonian agents; agents for treating cardiovascular disease such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and statins; agents for treating liver disease such as corticosteroids, cholestyramine, interferons, and anti-viral agents; agents for treating blood disorders such as corticosteroids, anti-leukemic agents, and growth factors; and agents for treating immunodeficiency disorders such as gamma globulin.

Additionally, chemotherapeutic agents include pharmaceutically acceptable salts, acids or derivatives of any of chemotherapeutic agents, described herein, as well as combinations of two or more of them.

For treating an inflammatory disease or an autoimmune disease, a compound of formula (I) or a pharmaceutically acceptable salt thereof may be co-administered with methotrexate, tofacitinib, 6-mercaptopurine, azathioprine sulphasalazine, mesalazine, olsalazine chloroquinine/hydroxychloroquinine, penicillamine, aurothiomalate (intramuscular and oral), azathioprine, cochicine, corticosteroids (oral, inhaled, and local injection), a beta-2 adrenoreceptor agonist (salbutamol, terbutaline, salmeteral), a xanthine (theophylline, aminophylline), cromoglycate, nedocromil, ketotifen, ipratropium and oxitropium, cyclosporin, FK506, rapamycin, mycophenolate mofetil, leflunomide, an NSAID (e.g. ibuprofen), a corticosteroid (e. g. prednisolone), a phosphodiesterase inhibitor, an adensosine agonist, an antithrombotic agent, a complement inhibitor, an adrenergic agent, an agent that interferes with signalling by proinflammatory cytokines such as TNF or IL-1 (e.g., a NIK, IKK, p38 or MAP kinase inhibitor), an IL-1 converting enzyme inhibitor, a T-cell signalling inhibitor (e.g. a kinase inhibitor), a metalloproteinase inhibitor, sulfasalazine, a 6-mercaptopurine, an angiotensin converting enzyme inhibitor, a soluble cytokine receptor (e.g. soluble p55 or p75 TNF receptors and the derivatives p75TNFRigG (etanercept) and p55TNFRigG (Lenercept), siL-1RI, siL-1RII, siL-6R), an antiinflammatory cytokine (e.g. IL-4, IL-10, IL-11, IL-13 and TGF), celecoxib, folic acid, hydroxychloroquine sulfate, rofecoxib, etanercept, infliximab, adalimumab, certolizumab, tocilizumab, abatacept, naproxen, valdecoxib, sulfasalazine, methylprednisolone, meloxicam, methylprednisolone acetate, gold sodium thiomalate, aspirin, triamcinolone acetonide, propoxyphene napsylate/apap, folate, nabumetone, diclofenac, piroxicam, etodolac, diclofenac sodium, oxaprozin, oxycodone HCl, hydrocodone bitartrate/apap, diclofenac sodium/misoprostol, fentanyl, anakinra, tramadol HCl, salsalate, sulindac, cyanocobalamin/fa/pyridoxine, acetaminophen, alendronate sodium, prednisolone, cortisone, betamethasone, morphine sulfate, lidocaine hydrochloride, indomethacin, glucosamine sulf/chondroitin, amitriptyline HCl, sulfadiazine, oxycodone HCVacetaminophen, olopatadine HCl misoprostol, naproxen sodium, omeprazole, cyclophosphamide, rituximab, IL-1 TRAP, MRA, CTLA4-IG, IL-18 BP, anti-IL-12, Anti-ILLS, BIRB-796, SCI0-469, VX-702, AMG-548, VX-740, Roflumilast, IC-485, CDC-801, S1P1 agonists (such as FTY720), a PKC family inhibitor (e.g. Ruboxistaurin or AEB-071) or Mesopram. In certain embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof may be co-administered with methotrexate or leflunomide. In moderate or severe rheumatoid arthritis cases, a compound of formula (I) or a pharmaceutically acceptable salt thereof may be co-administered with cyclosporine and anti-TNF antibodies as noted above. A compound of formula (I) or a pharmaceutically acceptable salt thereof may also be co-administered with: budenoside; epidermal growth factor; a corticosteroid; cyclosporin, sulfasalazine; an aminosalicylate; 6-mercaptopurine; azathioprine; metronidazole; a lipoxygenase inhibitor; mesalamine; olsalazine; balsalazide; an antioxidant; a thromboxane inhibitor; an IL-1 receptor antagonist; an anti-IL-1 monoclonal antibody; an anti-IL-6 monoclonal antibody; a growth factor; an elastase inhibitor; a pyridinyl-imidazole compound; an antibody to or antagonist of other human cytokines or growth factors (e.g. TNF, LT, IL-1, IL-2, IL-6, IL-7, IL-8, IL-12, IL-15, IL-16, IL-23, EMAP-II, GM-CSF, FGF, and PDGF); a cell surface molecule (e.g. CD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40, CD45, CD69, or CD90 or their ligands); methotrexate; cyclosporine; FK506; rapamycin; mycophenolate mofetil; leflunomide; an NSAID (e.g. ibuprofen); a corticosteroid (e.g. prednisolone); a phosphodiesterase inhibitor; an adenosine agonist; an antithrombotic agent; a complement inhibitor, an adrenergic agent; an agent that interferes with signalling by proinflammatory cytokines such as TNF 5 or IL-1 (e.g. a NIK, IKK, or MAP kinase inhibitor); an IL-1 converting enzyme inhibitor; a TNF converting enzyme inhibitor; a T-cell signalling inhibitor such as kinase inhibitors; a metalloproteinase inhibitor; sulfasalazine; azathioprine; a 6-mercaptopurine; an angiotensin converting enzyme inhibitor; a soluble cytokine receptor (e.g. soluble p55 or p75 TNF receptors, siL-1RI, siL-1RII, siL-6R), and an antiinflammatory cytokine (e.g. IL-4, IL-10, IL-11, IL-13 or TGF).

For treating Crohn's disease, a compound of formula (I) or a pharmaceutically acceptable salt thereof may be co-administered with a TNF antagonist (e.g. an anti-TNF antibody), D2E7 (adalimumab), CA2 (infliximab), CDP 571, a TNFR-Ig construct, (p75TNFRigG (etanercept)), a p55TNFRigG (LENERCEPT™) inhibitor, or a PDE4 inhibitor.

For treating inflammatory bowel disease, a compound of formula (I) or a pharmaceutically acceptable salt thereof may be co-administered with a corticosteroid (e.g. budenoside or dexamethasone); sulfasalazine, 5-aminosalicylic acid; olsalazine; an agent that interferes with synthesis or action of proinflammatory cytokines such as IL-1 (e.g. an IL-1 converting enzyme inhibitor or IL-Ira); a T cell signaling inhibitor (e.g. a tyrosine kinase inhibitor); 6-mercaptopurine; IL-11; mesalamine; prednisone; azathioprine; mercaptopurine; infliximab; methylprednisolone sodium succinate; diphenoxylate/atrop sulfate; loperamide hydrochloride; methotrexate; omeprazole; folate; ciprofloxacin/dextrose-water; hydrocodone bitartrate/apap; tetracycline hydrochloride; fluocinonide; metronidazole; thimerosal/boric acid; cholestyramine/sucrose; ciprofloxacin hydrochloride; hyoscyamine sulfate; meperidine hydrochloride; midazolam hydrochloride; oxycodone HCl/acetaminophen; promethazine hydrochloride; sodium phosphate; sulfamethoxazole/trimethoprim; celecoxib; polycarbophil; propoxyphene napsylate; hydrocortisone; multivitamins; balsalazide disodium; codeine phosphate/apap; colesevelam HCl; cyanocobalamin; folic acid; levofloxacin; methylprednisolone; natalizumab or interferon-gamma.

For treating multiple sclerosis, a compound of formula (I) or a pharmaceutically acceptable salt thereof may be co-administered with a corticosteroid; prednisolone; methylprednisolone; azathioprine; cyclophosphamide; cyclosporine; methotrexate; 4-aminopyridine; tizanidine; interferon-la (AVONEX®; Biogen); interferon-lb (BETASERON®; Chiron/Berlex); interferon-n3) (Interferon Sciences/Fujimoto), interferon-(Alfa Wassermnnann/J&J), interferon IA-IF (Serono/Inhale Therapeutics), Peginterferon 2b (Enzon/Schering-Plough), Copolymer 1 (Cop-1; COPAXONE®; Teva Pharmaceutical Industries, Inc.); hyperbaric oxygen; intravenous immunoglobulin; cladribine; an antibody to or antagonist of other human cytokines or growth factors and their receptors (e.g. TNF, LT, IL-1, IL-2, IL-6, IL-7, IL-8, IL-12, IL-23, 1L-15, IL-16, EMAP-II, GM-CSF, FGF, or PDGF).

For treating AIDS a compound of formula (I) or a pharmaceutically acceptable salt thereof may be co-administered with antibodies to cell surface molecules such as CD2, CD3, CD4, CD8, CD19, CD20, CD25, CD28, CD30, CD40, CD45, CD69, CD80, CD86, CD90 or their ligands. A compound of Formula (I) or a pharmaceutically acceptable salt thereof may also be co-administered with methotrexate, cyclosporine, FK506, rapamycin, mycophenolate mofetil, leflunomide, an S1P1 agonist, an NSAID (e.g. ibuprofen), a corticosteroid (e.g. prednisolone), a phosphodiesterase inhibitor, an adensosine agonist, an antithrombotic agent, a complement inhibitor, an adrenergic agent, an agent that interferes with signalling by proinflammatory cytokines such as TNF or IL-1 (e.g., a NIK, IKK, p38 or MAP kinase inhibitor), an IL-1 converting enzyme inhibitor, a TACE inhibitor, a T-cell signaling inhibitor (e.g. a kinase inhibitor), a metalloproteinase inhibitor, sulfasalazine, azathioprine, a 6-mercaptopurine, an angiotensin converting enzyme inhibitor, a soluble cytokine receptor (e.g. soluble p55 or p75 TNF receptors, siL-1RI, siL-1RII, or siL-6R), or an antiinflammatory cytokine (e.g. IL-4, IL-10, IL-13 or TGF).

A compound of formula (I) or a pharmaceutically acceptable salt thereof may also be co-administered with agents, such as alemtuzumab, dronabinol, daclizumab, mitoxantrone, xaliproden hydrochloride, fampridine, glatiramer acetate, natalizumab, sinnabidol, immunokine NNSO3, ABR-215062, AnergiX.MS, chemokine receptor antagonists, BBR-2778, calagualine, CPI-1189, LEM (liposome encapsulated mitoxantrone), THC.CBD (cannabinoid agonist), MBP-8298, mesopram (PDE4 inhibitor), MNA-715, an anti-IL-6 receptor antibody, neurovax, pirfenidone allotrap 1258 (RDP-1258), sTNF-RI, talampanel, teriflunomide, TGF-beta2, tiplimotide, a VLA-4 antagonist (e.g. TR-14035, VLA4 Ultrahaler, or Antegran-ELAN/Biogen), an interferon gamma antagonist, or an IL-4 agonist.

For treating ankylosing spondylitis a compound of formula (I) or a pharmaceutically acceptable salt thereof may be co-administered with ibuprofen, diclofenac, misoprostol, naproxen, meloxicam, indomethacin, diclofenac, celecoxib, rofecoxib, sulfasalazine, methotrexate, azathioprine, minocyclin, prednisone, an anti-TNF antibody, D2E7 (HUMIRA®), CA2 (infliximab), CDP 571, a TNFR-Ig construct, (p75TNFRigG (ENBREL®), or p55TNFRigG (LENERCEPT®).

For treating asthma a compound of formula (I) or a pharmaceutically acceptable salt thereof may be co-administered with albuterol, salmeterol/fluticasone, montelukast sodium, fluticasone propionate, budesonide, prednisone, salmeterol xinafoate, levalbuterol HCl, albuterol sulfate/ipratropium, prednisolone sodium phosphate, triamcinolone acetonide, beclomethasone dipropionate, ipratropium bromide, azithromycin, pirbuterol acetate, prednisolone, theophylline anhydrous, methylprednisolone sodium succinate, clarithromycin, zafirlukast, formoterol fumarate, influenza virus vaccine, amoxicillin trihydrate, flunisolide, cromolyn sodium, fexofenadine hydrochloride, flunisolide/menthol, amoxicillin/clavulanate, levofloxacin, guaifenesin, dexamethasone sodium phosphate, moxifloxacin HCl, doxycycline hyclate, guaifenesin/d-methorphan, p-ephedrine/cod/-chlorphenir, gatifloxacin, cetirizine hydrochloride, mometasone furoate, salmeterol xinafoate, benzonatate, cephalexin, pe/hydrocodone/chlorphenir, cetirizine HCl/pseudoephed, phenylephrine/cod/promethazine, codeine/promethazine, cefprozil, dexamethasone, guaifenesin/pseudoephedrine, chlorpheniramine/hydrocodone, nedocromil sodium, terbutaline sulfate, epinephrine, methylprednisolone, an anti-IL-13 antibody, or metaproterenol sulfate.

For treating COPD a compound of formula (I) or a pharmaceutically acceptable salt thereof may be co-administered with albuterol sulfate/ipratropium, ipratropium bromide, salmeterol/fluticasone, albuterol, salmeterol xinafoate, fluticasone propionate, prednisone, theophylline anhydrous, methylprednisolone sodium succinate, montelukast sodium, budesonide, formoterol fumarate, triamcinolone acetonide, levofloxacin, guaifenesin, azithromycin, beclomethasone dipropionate, levalbuterol HCl, flunisolide, ceftriaxone sodium, amoxicillin trihydrate, gatifloxacin, zafirlukast, amoxicillin/clavulanate, flunisolide/menthol, chlorpheniramine/hydrocodone, metaproterenol sulfate, methylprednisolone, mometasone furoate, p-ephedrine/cod/chlorphenir, pirbuterol acetate, p-ephedrine/loratadine, terbutaline sulfate, tiotropium bromide, (R,R)-formoterol, TgAAT, cilomilast, or roflumilast.

For treating psoriasis, a compound of formula (I) or a pharmaceutically acceptable salt thereof may be co-administered with calcipotriene, clobetasol propionate, triamcinolone acetonide, halobetasol propionate, tazarotene, methotrexate, fluocinonide, betamethasone diprop augmented, fluocinolone acetonide, acitretin, tar shampoo, betamethasone valerate, mometasone furoate, ketoconazole, pramoxine/fluocinolone, hydrocortisone valerate, flurandrenolide, urea, betamethasone, clobetasol propionate/emoll, fluticasone propionate, azithromycin, hydrocortisone, moisturizing formula, folic acid, desonide, pimecrolimus, coal tar, diflorasone diacetate, etanercept folate, lactic acid, methoxsalen, he/bismuth subgal/znox/resor, methylprednisolone acetate, prednisone, sunscreen, halcinonide, salicylic acid, anthralin, clocortolone pivalate, coal extract, coal tar/salicylic acid, coal tar/salicylic acid/sulfur, desoximetasone, diazepam, emollient, fluocinonide/emollient, mineral oil/castor oil/na lact, mineral oil/peanut oil, petroleum/isopropyl myristate, psoralen, salicylic acid, soap/tribromsalan, thimerosal/boric acid, celecoxib, infliximab, cyclosporine, alefacept, efalizumab, tacrolimus, pimecrolimus, PUVA, UVB, sulfasalazine, ABT-874 or ustekinamab.

For treating psoriatic arthritis, a compound of formula (I) or a pharmaceutically acceptable salt thereof may be co-administered with methotrexate, etanercept, rofecoxib, celecoxib, folic acid, sulfasalazine, naproxen, leflunomide, methylprednisolone acetate, indomethacin, hydroxychloroquine sulfate, prednisone, sulindac, betamethasone diprop augmented, infliximab, methotrexate, folate, triamcinolone acetonide, diclofenac, dimethylsulfoxide, piroxicam, diclofenac sodium, ketoprofen, meloxicam, methylprednisolone, nabumetone, tolmetin sodium, calcipotriene, cyclosporine, diclofenac sodium/misoprostol, fluocinonide, glucosamine sulfate, gold sodium thiomalate, hydrocodone bitartrate/apap, ibuprofen, risedronate sodium, sulfadiazine, thioguanine, valdecoxib, alefacept, D2E7 (adalimumab), or efalizumab.

For treating lupus, a compound of formula (I) or a pharmaceutically acceptable salt thereof may be co-administered with an NSAID (e.g. diclofenac, naproxen, ibuprofen, piroxicam, or indomethacin); a COX2 inhibitor (e.g. celecoxib, rofecoxib, or valdecoxib); an anti-malarial (e.g. hydroxychloroquine); a steroid (e.g. prednisone, prednisolone, budenoside, or dexamethasone); a cytotoxic (e.g. azathioprine, cyclophosphamide, mycophenolate mofetil, or methotrexate); an inhibitor of PDE4, or a purine synthesis inhibitor (e.g. Cellcept®). For example, a compound of formula (I) or a pharmaceutically acceptable salt thereof may be co-administered with sulfasalazine, 5-aminosalicylic acid, olsalazine, Imuran®, an agent that interferes with the synthesis, production, or action of a proinflammatory cytokine (e.g. IL-1), or a caspase inhibitor (e.g. a IL-1 converting enzyme inhibitor or IL-Ira).

A compound of formula (I) or a pharmaceutically acceptable salt thereof may also be co-administered with a T cell signaling inhibitor (e.g. a tyrosine kinase inhibitor), or a molecule that targets T cell activation (e.g. CTLA-4-IgG, an anti-B7 family antibody, or an anti-PD-1 family antibody).

A compound of formula (I) or a pharmaceutically acceptable salt thereof can also be co-administered with an IL-11 antibody, an anti-cytokine antibody (e.g. fonotolizumab (anti-IFNg antibody)), or an anti-receptor receptor antibodies (e.g. an anti-IL-6 receptor antibody or an antibody to a B-cell surface molecule).

A compound of formula (I) or a pharmaceutically acceptable salt thereof can also be co-administered with LJP 394 (abetimus), an agent that depletes or inactivates B-cells (e.g. Rituximab (anti-CD20 antibody) or lymphostat-B (anti-BlyS antibody)), a TNF antagonist (e.g. an anti-TNF antibody), D2E7 (adalimumab), CA2 (infliximab), CDP 571, a TNFR-Ig construct, (p75TNFRigG (etanercept), or p55TNFRigG (LENERCEPT™).

A compound of formula (I) or a pharmaceutically acceptable salt thereof can also be co-administered with one or more agents used in the prevention or treatment of AIDS: an HIV reverse transcriptase inhibitor, an HIV protease inhibitor, an immunomodulator, or another retroviral drug. Examples of reverse transcriptase inhibitors include, but are not limited to, abacavir, adefovir, didanosine, dipivoxil delavirdine, efavirenz, emtricitabine, lamivudine, nevirapine, rilpivirine, stavudine, tenofovir, zalcitabine, and zidovudine. Examples of protease inhibitors include, but are not limited to, amprenavir, atazanavir, darunavir, indinavir, fosamprenavir, lopinavir, nelfinavir, ritonavir, saquinavir, and tipranavir. Examples of other retroviral drugs include, but are not limited to, elvitegravir, enfuvirtide, maraviroc and raltegravir.

For treating type II diabetes, hepatic steatosis, insulin resistance, metabolic syndrome or a related disorder, a compound of formula (I) or a pharmaceutically acceptable salt thereof may be co-administered with insulin or insulins that have been modified to improve the duration of action in the body; agents that stimulate insulin secretion such as acetohexamide, chlorpropamide, glyburide, glimepiride, glipizide, glicazide, glycopyramide, gliquidone, rapaglinide, nataglinide, tolazamide or tolbutamide; agents that are glucagon-like peptide agonists such as exanatide, liraglutide or taspoglutide; agents that inhibit dipeptidyl-peptidase IV such as vildagliptin, sitagliptin, saxagliptin, linagliptin, allogliptin or septagliptin; agents that bind to the peroxisome proliferator-activated receptor gamma such as rosiglitazone or pioglitazone; agents that decrease insulin resistance such as metformin; or agents that reduce glucose absorbance in the small intestine such as acarbose, miglitol or voglibose.

For treating acute kidney disorders or a chronic kidney disease, a compound of formula (I) or a pharmaceutically acceptable salt thereof may be co-administered with dopamine, a diuretic (e.g. furosemide), bumetanide, thiazide, mannitol, calcium gluconate, sodium bicarbonate, albuterol, paricalcitol, doxercalciferol, cinacalcet, or bardoxalone methyl.

The amount of both the compound of formula (I) or salt thereof and additional agent (in those compositions which comprise an additional therapeutic agent as described above) that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. In certain embodiments, compositions of this invention are formulated such that a dosage of between 0.01-100 mg/kg body weight/day of an inventive can be administered.

The additional therapeutic agent and the compound of formula (I) may act synergistically. Therefore, the amount of additional therapeutic agent in such compositions may be less than that required in a monotherapy utilizing only that therapeutic agent, or there may be fewer side effects for the patient given that a lower dose is used. In certain embodiments, in such compositions a dosage of between 0.01-1,000 μg/kg body weight/day of the additional therapeutic agent can be administered.

Provided herein are methods of extending the duration of response to a cytotoxic agent in an individual with cancer comprising administering to the individual (a) an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and (b) an effective amount of the cytotoxic agent.

In certain embodiments of any of the methods, the cytotoxic agent is a targeted therapy. In certain embodiments, the targeted therapy is one or more of an EGFR antagonist, RAF inhibitor, and/or PI3K inhibitor.

In certain embodiments of any of the methods, the targeted therapy is an EGFR antagonist. In certain embodiments of any of the methods, the EGFR antagonist is N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine and/or a pharmaceutical acceptable salt thereof. In certain embodiments, the EGFR antagonist is N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine. In certain embodiments, the EGFR antagonist is N-(4-(3-fluorobenzyloxy)-3-chlorophenyl)-6-(5-((2-(methylsulfonyl)ethylamino)methyl)furan-2-yl)quinazolin-4-amine,di4-methylbenzenesulfonate or a pharmaceutically acceptable salt thereof (e.g., lapatinib).

In certain embodiments of any of the methods, targeted therapy is a RAF inhibitor. In certain embodiments, the RAF inhibitor is a BRAF inhibitor. In certain embodiments, the RAF inhibitor is a CRAF inhibitor. In certain embodiments, the BRAF inhibitor is vemurafenib. In certain embodiments, the RAF inhibitor is 3-(2-cyanopropan-2-yl)-N-(4-methyl-3-(3-methyl-4-oxo-3,4-dihydroquinazolin-6-ylamino)phenyl)benzamide or a pharmaceutically acceptable salt thereof (e.g., AZ628 (CAS#878739-06-1)).

In certain embodiments of any of the methods, the targeted therapy is a PI3K inhibitor.

In certain embodiments of any of the methods, the cytotoxic agent is chemotherapy. In certain embodiments of any of the methods, the chemotherapy is a taxane. In certain embodiments, the taxane is paclitaxel. In certain embodiments, the taxane is docetaxel.

In certain embodiments of any of the methods, the cytotoxic agent is a platinum agent. In certain embodiments, the platinum agent is carboplatin. In certain embodiments, the platinum agent is cisplatin. In certain embodiments of any of the methods, the cytotoxic agent is a taxane and a platinum agent. In certain embodiments, the taxane is paclitaxel. In certain embodiments, the taxane is docetaxel. In certain embodiments, the platinum agent is carboplatin. In certain embodiments, the platinum agent is cisplatin.

In certain embodiments of any of the methods, the cytotoxic agent is a vinca alkyloid. In certain embodiments, the vinca alkyloid is vinorelbine. In certain embodiments of any of the methods, the chemotherapy is a nucleoside analog. In certain embodiments, the nucleoside analog is gemcitabine.

In certain embodiments of any of the methods, the cytotoxic agent is radiotherapy.

In certain embodiments of any of the methods, the compound of formula (I) or a pharmaceutically acceptable salt thereof is concomitantly administered with the cytotoxic agent (e.g., targeted therapy, chemotherapy, and/or radiotherapy). In certain embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered prior to and/or concurrently with the cytotoxic agent (e.g., targeted therapy, chemotherapy, and/or radiotherapy).

EXEMPLIFICATION

As depicted in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. It will be appreciated that, although the general methods depict the synthesis of certain compounds of the present invention, the following general methods, and other methods known to one of ordinary skill in the art, can be applied to all compounds and subclasses and species of each of these compounds, as described herein.

Representative Compounds of formula (I) were prepared according to the scheme shown above. Intermediate A (prepared as described below) was converted into the corresponding methyl ester under Pd-catalyzed carbonylation conditions, and the resultant intermediates were alkylated with various R¹-halides. Hydrolysis of those esters simultaneously removed the tosyl protecting group and revealed the carboxylic acid, which was coupled with various amines to yield compounds of formula (I).

Representative compounds of formula (I) were prepared according to the scheme shown above. Intermediate A (prepared as described below) was alkylated with various R¹-halides before being converted into the corresponding carboxylic acids under Pd-catalyzed carbonylation conditions. Subsequent amide bond formation, followed by hydrolytic removal of the tosyl group, yielded compounds of formula (I).

Representative compounds of formula (I) were prepared according to the scheme shown above. Variously N-substituted derivatives of tert-butyl 4-(2-(7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-carboxamido)ethyl)piperidine-1-carboxylate (prepared as in Generic Scheme A) were protected with tosyl chloride under basic conditions. The resultant compounds were alkylated with R^(c)-halides on the amide nitrogen before acidic removal of the Boc protecting group. Reductive amination with various aldehydes introduced substituents on the piperidine, and subsequent hydrolytic removal of the tosyl group yielded compounds of formula (I).

Representative compounds of formula (I) were prepared according to the scheme shown above. Variously pyrrolopyridone N-substituted derivatives of tert-butyl 4-((N-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-carboxamido)methyl)piperidine-1-carboxylate (prepared as in Generic Scheme A) were deprotected under acidic conditions. Reductive amination of the resultant amines with various aldehydes yielded compounds of formula (I).

Representative compounds of formula (I) were prepared according to the scheme shown above. Variously pyrrolopyridone N-substituted derivatives of tert-butyl 4-(N-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-carboxamido)piperidine-1-carboxylate (prepared as in Generic Scheme A) were deprotected under acidic conditions. Reductive amination of the resultant amines with various aldehydes yielded compounds of formula (I).

Representative compounds of formula (I) were prepared according to the scheme shown above. Variously pyrrolopyridone N-substituted derivatives of tert-butyl 4-methyl-4-((7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-carboxamido)methyl)piperidine-1-carboxylate (prepared as in Generic Scheme A) were deprotected under acidic conditions. Reductive amination of the resultant amines with various aldehydes yielded compounds of formula (I).

Representative compounds of formula (I) were prepared according to the scheme shown above. Variously pyrrolopyridone N-substituted derivatives of N-methyl-7-oxo-N-(piperidin-4-yl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-carboxamide hydrochloride (prepared as in Generic Scheme A) were alkylated on the piperidine nitrogen to yield compounds of formula (I).

Representative compounds of formula (I) were prepared according to the scheme shown above. Intermediate D (prepared as described below) was converted into compounds of formula (I) by Pd-catalyzed amino carbonylation in the presence of variously substituted amines.

Step 1:

2-methoxy-4-methyl-3-nitropyridine

A solution of 2-chloro-4-methyl-3-nitropyridine (250 g, 1.45 mol) in methanol (1.0 L) was added dropwise (2 h) to a stirred and cooled (0° C.) solution of sodium methoxide (250 g, 4.63 mol) in methanol (850 mL). After addition, the mixture was heated to reflux for 23 h, at which time TLC indicated the reaction had gone to completion. The mixture was concentrated under reduced pressure to a volume of approximately 900 mL, and quenched by addition of water (1.5 L). The resulting solid was collected by filtration, washed with water and dried under reduced pressure to give the title compound (250 g, 100% yield) as a brown solid. ¹H NMR (400 MHz, DMSO-d6): δ 8.22 (d, J=5.2 Hz, 1 H), 7.10 (d, J=5.6 Hz, 1 H), 3.92 (s, 3 H), 2.26 (s, 3 H).

Step 2:

5-bromo-2-methoxy-4-methyl-3-nitropyridine

Sodium acetate (365 g, 5.37 mol) was added to a stirred solution of 2-methoxy-4-methyl-3-nitropyridine (250 g, 1.49 mol) in acetic acid (1.5 L) at ambient temperature and then Br₂ (639 g, 4.00 mol) was added dropwise (30 min). After addition, the mixture was heated at 80° C. for 12 h, at which time TLC indicated the reaction had gone to completion. The mixture was cooled (0° C.) and quenched by sequential addition of 10% aqueous (1.5 L) and saturated aqueous Na₂SO₃ (1.5 L). The resulting solid was collected by filtration washed with water, and dried under reduced pressure to give the title compound (302 g, 82.2% yield) as a light yellow solid. ¹H NMR (400 MHz, DMSO-d6): δ 8.25 (s, 1 H), 3.94 (s, 3 H), 2.29 (s, 3 H).

Step 3:

(E)-2-(5-bromo-2-methoxy-3-nitro-4-pyridyl)-N,N-dimethyl-ethenamine

DMF-DMA (600 mL) was slowly added to a stirred and heated (80° C.) solution of 5-bromo-2-methoxy-4-methyl-3-nitropyridine (134 g, 0.54 mol) in DMF (1.1 L). After addition, the mixture was heated at 95° C. for 5 h, at which time TLC indicated the reaction had gone to completion. The mixture was cooled to room temperature and poured into ice-cold water (3 L). The resulting red solid was collected by filtration, washed with water, and dried under reduced pressure to give the title compound (167 g, 100% yield) as red solid. ¹H NMR (400 MHz, DMSO-d6): δ 8.24 (s, 1 H), 7.05 (d, J=13.6 Hz, 1 H), 7.05 (d, J=13.6 Hz, 1 H), 4.80 (d, J=13.2 Hz, 1 H), 3.88 (s, 3 H), 2.90 (s, 6 H).

Step 4:

4-bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine

A mixture of 2-(5-bromo-2-methoxy-3-nitropyridin-4-yl)-N,N-dimethylethenamine (50.0 g, 165 mmol), Fe (50.0 g, 893 mmol) and NH₄Cl (50.0 g, 943 mmol) in methanol/H₂O (1900/250 mL) was heated at reflux for 7 h, at which time LCMS indicated that the reaction had gone to completion. The mixture was filtered while hot and the cake was washed with methanol (3×200 mL). The combined filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (petroleum ether: Ethyl acetate=5:1) to give the crude product. This crude material was triturated with acetonitrile to give the title compound (37.4 g, 99.5% yield) as a light brown solid. LCMS M/Z (M+H) 226.7, 228.7.

Step 5:

4-bromo-7-methoxy-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridine

A solution of 4-bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine (34.3 g, 0.15 mol) in THF (700 mL) was added dropwise to a stirred and cooled (0° C.) solution of sodium hydride (60%, 19.2 g, 0.48 mol) in THF (700 mL). After addition, the mixture was stirred at room temperature for 1 h, and then cooled again to 0° C. Tosyl chloride (38.0 g, 0.20 mol) in THF (700 mL) was added dropwise and the resulting mixture was stirred at ambient temperature for 2 h. The reaction was quenched by addition of saturated aqueous ammonium chloride (1.0 L), and then extracted with ethyl acetate (3×600 mL). The combined organic extracts were dried over Na₂SO₄ and concentrated under reduced pressure. The residue was triturated with acetonitrile to give the title compound (51.2 g, 88.9% yield) as a brown solid. This crude material was used in the next step without further purification.

Step 6:

4-bromo-1-(p-tolylsulfonyl)-6H-pyrrolo[2,3-c]pyridin-7-one

HBr (40% aqueous, 1.1 L) was added to a solution of 4-bromo-7-methoxy-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridine (102.5 g, 0.27 mol) in ethanol (200 mL). After addition, the mixture was heated at 90° C. for 2 h, at which time TLC indicated that the reaction had gone to completion. The mixture was cooled to 0° C. and the resulting white solid was collected by filtration. This solid was washed with water and dried under vacuum to give the title compound (Intermediate A) (87.5 g, 88.6% yield) as a light brown solid. ¹H NMR (400 MHz, DMSO-d6): δ 11.48 (s, 1 H), 8.01 (d, J=3.6 Hz, 1 H), 8.90 (d, J=8.0 Hz, 2 H), 7.38 (d, J=8.0 Hz, 2 H), 7.32 (s, 1 H), 6.57 (d, J=3.2 Hz, 1 H), 2.34 (s, 3 H).

Step 7:

methyl 7-oxo-1-(p-tolylsulfonyl)-6H-pyrrolo[2,3-c]pyridine-4-carboxylate

[1,1′-bis(diphenylphosphino)ferrocene]palladium(ii) dichloride (5.0 g, 8.5 mmol) was added to a mixture of 4-bromo-1-(p-tolylsulfonyl)-6H-pyrrolo[2,3-c]pyridin-7-one (10.0 g, 27.3 mmol), Et₃N (20.0 mL, 143.5 mmol) in methanol (1 L). After addition, the mixture was stirred under CO atmosphere (50 psi) at 80° C. for 24 h, at which time TLC (petroleum ether:ethyl acetate=1:1) showed the completion of the reaction. The resulting mixture was concentrated under reduced pressure and the residue was purified by flash column (petroleum ether: ethyl acetate=5:1 to 3:1) to give the title compound (Intermediate B) (7.5 g, 79.5% yield) as a brown solid. ¹H NMR (400 MHz, DMSO-d6): δ 11.79 (s, 1 H), 8.03 (d, J=3.6 Hz, 1 H), 7.88 (d, J=8.4 Hz, 2 H), 7.80 (s, 1 H), 7.37 (d, J=8.0 Hz, 2 H), 7.05 (d, J=3.2 Hz, 1 H), 3.77 (s, 3 H), 2.33 (s, 3 H).

Step 8:

methyl 6-methyl-7-oxo-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridine-4-carboxylate

Methyl iodide (18.1 g, 127.24 mmol) was added dropwise to a stirred solution of methyl 7-oxo-1-(p-tolylsulfonyl)-6H-pyrrolo[2,3-c]pyridine-4-carboxylate (11.6 g, 33.49 mmol) and Cs₂CO₃ (13.1 g, 40.18 mmol) in dioxane (230 mL). After addition, the resulting mixture was stirred at room temperature for 4 hr, at which time TLC indicated the reaction was completed. The solid was removed by filtration and the filtrate was concentrated. The residue was dissolved in ethyl acetate (250 mL) and washed with water (50 mL×2). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give the title compound (11.0 g, 91.1% yield) as a white solid. This crude was used into next step without further purification. LCMS M/Z (M+H) 360.9.

Step 9:

6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carboxylic acid

Sodium hydroxide (6.0 g, 150.0 mmol) was added in portions to a stirred solution of methyl 6-methyl-7-oxo-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridine-4-carboxylate (12.0 g, 33.3 mmol) in methanol/water (260/30 mL). After addition, the mixture was stirred at 80° C. for 2 h, at which time LCMS indicated the reaction had gone to completion. After cooling, the mixture was concentrated under reduced pressure. The residue was dissolved in water (30 mL) and the aqueous solution was acidified to pH 3-4 using 5 N hydrochloric acid. The resulting precipitate was collected by filtration, washed with water, and dried under reduced pressure to give the title compound (Intermediate C) (4.3 g, 67.2% yield) as a brown solid. This crude material was used in the next step without further treatment. LCMS M/Z (M+H) 192.8.

General Procedure for the Preparation of Intermediates D, E

4-bromo-6-methyl-1-(p-tolylsulfonyl)pyrrolo[2,3-e]pyridin-7-one

Methyl iodide (24.5 g, 172.8 mmol) was added dropwise to a stirred suspension of 4-bromo-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one (Intermediate A) (16.7 g, 45.5 mmol) and cesium carbonate (17.8 g, 54.6 mmol) in dioxane (250 mL). After addition, the reaction mixture was stirred at room temperature for 18 h, at which time LCMS indicated the reaction had gone to completion. The solvent was evaporated under reduced pressure, and the residue was diluted with water (200 mL). The mixture was extracted with EtOAc (3×200 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate=3:1) to give the title compound (Intermediate D) (14.0 g, 81.4% yield) as a brown solid. ¹H NMR (400 MHz, DMSO-d6): δ 8.03 (d, J=3.6 Hz, 1 H), 7.92 (d, J=8.4 Hz, 2 H), 7.78 (s, 1 H), 7.39 (d, J=8.4 Hz, 2 H), 6.57 (d, J=3.6 Hz, 1 H), 3.35 (s, 3 H), 2.35 (s, 3 H).

6-methyl-7-oxo-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridine-4-carboxylic acid

A disposable tube was charged with 4-bromo-6-methyl-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridin-7-one (Intermediate D), 2 g, 5.25 mmol), 1,3-bis(dicyclohexylphosphino)propane (0.642 g, 1.049 mmol), palladium acetate (0.118 g, 0.525 mmol), and potassium carbonate (1.450 g, 10.49 mmol) before being evacuated and purged with carbon monoxide three times. Water (0.189 ml, 10.49 mmol) and dimethylsulfoxide (5 mL) were added, and the mixture was stirred at 100° C. for 6 h. The reaction mixture was cooled and diluted with ethyl acetate (100 mL). The crude product was extracted with 1 N aqueous sodium hydroxide. This aqueous extract was then acidified using 1 N hydrochloric acid resulting in formation of a precipitate. This material was collected and lyophilized to yield title compound (Intermediate E) (1.08 g, 59%) as a grey amorphous solid that was used crude in subsequent reactions. LCMS M/Z (M+H) 347.

General Procedure for Intermediate F

Step 1:

5-bromo-2-methoxy-3-nitropyridine

Sodium methoxide (17.2 g, 318.4 mmol) was added to a stirred solution of 5-bromo-2-chloro-3-nitropyridine (15.0 g, 64.2 mmol) in methanol (125 mL). After addition, the reaction mixture was heated at reflux for 2 h. The mixture was concentrated under reduced pressure, and the residue was diluted with water (200 mL). The resulting precipitate was collected by filtration, washed with water, and dried under reduced pressure to give the title compound (12.0 g, 81.5% yield) as a brown solid. ¹H NMR (400 MHz, CDCl₃): δ 8.43 (d, J=2.4 Hz, 1 H), 8.38 (d, J=2.0 Hz, 1 H), 4.09 (s, 3 H).

Step 2:

4-bromo-7-methoxy-2-methyl-1H-pyrrolo[2,3-c]pyridine

Isopropenyl magnesium bromide (0.5 M in THF, 105.0 mL, 55.0 mmol) was added dropwise to a stirred and cooled (−78° C.) solution of 5-bromo-2-methoxy-3-nitropyridine (4.0 g, 17.1 mmol) in THF (40 mL). After addition, the resulting mixture was allowed to warm to room temperature gradually and stirred for an additional 3 h. The reaction mixture was quenched by addition of 1 M aqueous ammonium chloride (150 mL), and then extracted with ethyl acetate (3×100 mL). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate=10:1) to give the title compound (1.65 g, 39.9% yield) as brown oil. LCMS M/Z (M+H) 240/242.

Step 3:

4-bromo-2-methyl-1,6-dihydropyrrolo[2,3-c]pyridin-7-one

Hydrogen bromide (40% aqueous, 20 mL) was added to a solution of 4-bromo-7-methoxy-2-methyl-1H-pyrrolo[2,3-c]pyridine (1.65 g, 6.8 mmol) in ethanol (10 mL). After addition, the reaction mixture was heated at 90° C. for 15 h, at which time TLC indicated the reaction had gone to completion. The mixture was cooled to 0° C. and the resulting solid was collected by filtration. This solid was washed with water and dried to give title compound (0.9 g, 57.9% yield) as a brown solid. ¹H NMR (400 MHz, DMSO-d6): δ 12.06 (s, 1 H), 11.00 (s, 1 H), 7.03 (s, 1 H), 5.97 (s, 1 H), 2.29 (s, 3 H). LCMS M/Z (M+H) 226/228

Step 4:

6-allyl-2-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-carboxylic acid (Intermediate F)

To a solution of methyl 2-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-carboxylate (10.0 g, 48.5 mmol) in DMF (100 mL) was added K₂CO₃ (20.1 g, 145.0 mmol) and allyl bromide (5.9 g, 48.5 mmol). After addition, the mixture was stirred at ambient temperature for 12 h, at which time LCMS showed the completion of the reaction. The reaction mixture was diluted with ice-water (200 mL). The resulting precipitate was collected by filtration, washed with water and dried.

A suspension of the above crude product in methanol (150 mL) and was added KOH (10.9 g, 194 mmol) in water (50 mL). The mixture was heated at 50° C. for 4 h, at which time LCMS showed the completion of the reaction. Methanol was evaporated under reduced pressure, and the aqueous solution was acidified by adding 2 N HCl to pH 2. The resulting precipitate was collected by filtration and dried to give the title compound (Intermediate F) (10.2 g, 91% yield) as a grey solid.

Example 1 N-(2-dimethylaminoethyl)-6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carboxamide

To an 8 mL vial was added N,N-dimethylethane-1,2-diamine (26 mg, 0.30 mmol) followed by 6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carboxylic acid (Intermediate C, 0.80 mL, 0.20 mmol, 0.25 mol/L in DMF), HATU (0.48 mL, 0.24 mmol, 0.50 mol/L in DMF), and TEA (0.56 mL, 0.40 mmol). The reaction was capped and shaken at room temperature overnight. The reaction was then concentrated under reduced pressure and the residue was then partitioned between dichloromethane and water. The organic phase was separated and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (0-25/ACN/0.1% NH4OH in H2O) yielding N-(2-dimethylaminoethyl)-6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carboxamide, (21 mg, 40%). ¹H NMR (400 MHz, DMSO-d6) δ 12.07 (s, 1H), 7.86-7.68 (m, 2H), 7.33 (d, J=2.2 Hz, 1H), 6.70 (d, J=2.7 Hz, 1H), 3.55 (s, 3H), 3.37-3.31 (m, 2H), 2.40 (t, J=6.8 Hz, 2H), 2.19 (s, 6H). LCMS M/Z (M+H) 367.2.

The following compounds were prepared in a similar manner to Example 1: Examples 2-82

Example Compound Name NMR m/z 2 N-[2-(dimethylamino)-1- 1H NMR (400 MHz, DMSO) δ 12.07 (s, 1H), 277 methyl-ethyl]-6-methyl- 7.86-7.68 (m, 2H), 7.33 (d, J = 2.2 Hz, 1H), 7-oxo-1H-pyrrolo[2,3- 6.70 (d, J = 2.7 Hz, 1H), 3.55 (s, 3H), c]pyridine-4- 3.37-3.31 (m, 2H), 2.40 (t, J = 6.8 Hz, 2H), 2.19 (s, carboxamide 6H). 3 6-methyl-N-[(1-methyl- 1H NMR (400 MHz, DMSO) δ 12.07 (s, 1H), 303 4-piperidyl)methyl]-7- 7.86-7.68 (m, 2H), 7.33 (d, J = 2.2 Hz, 1H), oxo-1H-pyrrolo[2,3- 6.70 (d, J = 2.7 Hz, 1H), 3.55 (s, 3H), c]pyridine-4- 3.37-3.31 (m, 2H), 2.40 (t, J = 6.8 Hz, 2H), 2.19 (s, carboxamide 6H). 4 6-methyl-N-(1-methyl-4- 1H NMR (400 MHz, DMSO) δ 12.07 (s, 1H), 289 piperidyl)-7-oxo-1H- 7.86-7.68 (m, 2H), 7.33 (d, J = 2.2 Hz, 1H), pyrrolo[2,3-c]pyridine-4- 6.70 (d, J = 2.7 Hz, 1H), 3.55 (s, 3H), carboxamide 3.37-3.31 (m, 2H), 2.40 (t, J = 6.8 Hz, 2H), 2.19 (s, 6H). 5 6-methyl-7-oxo-N-[2-(1- 1H NMR (400 MHz, DMSO) δ 12.09 (s, 1H), 303 piperidyl)ethyl]-1H- 7.80 (s, 1H), 7.76-7.71 (m, 1H), pyrrolo[2,3-c]pyridine-4- 7.38-7.29 (m, 1H), 6.71 (s, 1H), 3.55 (s, 3H), carboxamide 3.42-3.33 (m, 2H), 2.48-2.35 (m, 6H), 1.55-1.45 (m, 4H), 1.45-1.34 (m, 2H). 6 6-methyl-N-(1- 1H NMR (400 MHz, DMSO) δ 12.07 (s, 1H), 275 methylpyrrolidin-3-yl)-7- 7.86-7.68 (m, 2H), 7.33 (d, J = 2.2 Hz, 1H), oxo-1H-pyrrolo[2,3- 6.70 (d, J = 2.7 Hz, 1H), 3.55 (s, 3H), c]pyridine-4- 3.37-3.31 (m, 2H), 2.40 (t, J = 6.8 Hz, 2H), 2.19 (s, carboxamide 6H). 7 6-methyl-N-[2-(1- 1H NMR (400 MHz, DMSO) δ 12.07 (s, 1H), 303 methylpyrrolidin-2- 7.86-7.68 (m, 2H), 7.33 (d, J = 2.2 Hz, 1H), yl)ethyl]-7-oxo-1H- 6.70 (d, J = 2.7 Hz, 1H), 3.55 (s, 3H), pyrrolo[2,3-c]pyridine-4- 3.37-3.31 (m, 2H), 2.40 (t, J = 6.8 Hz, 2H), 2.19 (s, carboxamide 6H). 8 6-methyl-N-(2- 1H NMR (400 MHz, DMSO) δ 12.07 (s, 1H), 305 morpholinoethyl)-7-oxo- 7.86-7.68 (m, 2H), 7.33 (d, J = 2.2 Hz, 1H), 1H-pyrrolo[2,3- 6.70 (d, J = 2.7 Hz, 1H), 3.55 (s, 3H), c]pyridine-4- 3.37-3.31 (m, 2H), 2.40 (t, J = 6.8 Hz, 2H), 2.19 (s, carboxamide 6H). 9 6-but-2-enyl-N-[3-(4- ¹H NMR (400 MHz, DMSO-d₆) δ 12.07 (s, 372 methylpiperazin-1- 1H), 7.93 (t, J = 5.5 Hz, 1H), 7.70 (s, 1H), yl)propyl]-7-oxo-1H- 7.33 (d, J = 2.8 Hz, 1H), 6.69 (d, J = 2.7 Hz, pyrrolo[2,3-c]pyridine-4- 1H), 5.67-5.59 (m, 2H), 4.58-4.51 (m, 2H), carboxamide 3.27 (d, J = 7.4 Hz, 4H), 2.74-2.69 (m, 2H), 2.30 (h, J = 7.8, 4.6 Hz, 6H), 2.13 (d, J = 4.3 Hz, 4H), 1.73-1.60 (m, 5H). 10 tert-butyl 3-[[(6-but-2- ¹H NMR (400 MHz, DMSO-d₆) δ 12.08 (s, 401 enyl-7-oxo-1H- 1H), 8.10 (t, J = 5.8 Hz, 1H), 7.71 (s, 1H), pyrrolo[2,3-c]pyridine-4- 7.34 (t, J = 2.6 Hz, 1H), 6.68 (dd, J = 2.8, 1.5 Hz, carbonyl)amino]methyl]azetidine- 1H), 5.70-5.53 (m, 2H), 4.55 (dd, J = 3.5, 1-carboxylate 1.9 Hz, 2H), 3.96-3.79 (m, 2H), 3.72-3.54 (m, 2H), 3.43 (t, J = 6.3 Hz, 2H), 2.81-2.65 (m, 1H), 1.73-1.59 (m, 3H), 1.36 (s, 9H). 11 6-but-2-enyl-N-[(1- ¹H NMR (400 MHz, DMSO-d₆) δ 12.12 (s, 343 methyl-4- 1H), 7.32 (d, J = 2.8 Hz, 1H), 7.25 (s, 1H), piperidyl)methyl]-7-oxo- 6.19 (d, J = 2.8 Hz, 1H), 5.75-5.48 (m, 2H), 1H-pyrrolo[2,3- 4.62-4.46 (m, 2H), 2.82 (s, 5H), 2.12 (s, 3H), c]pyridine-4- 1.89-1.69 (m, 4H), 1.68-1.59 (m, 3H), carboxamide 1.60-1.53 (m, 2H). 12 6-but-2-enyl-N-[2-(4- ¹H NMR (400 MHz, DMSO-d₆) δ 7.75 (t, J = 5.5 Hz, 358 methylpiperazin-1- 1H), 7.71 (s, 1H), 7.36 (d, J = 2.8 Hz, yl)ethyl]-7-oxo-1H- 1H), 6.71 (d, J = 2.8 Hz, 1H), 5.71-5.58 (m, pyrrolo[2,3-c]pyridine-4- 2H), 4.56 (dd, J = 3.7, 1.7 Hz, 2H), carboxamide 3.41-3.33 (m, 6H), 2.50-2.41 (m, 2H), 2.40-2.26 (m, 4H), 2.14 (s, 3H), 1.70-1.60 (m, 3H). 13 benzyl N-[2-[[6-[(E)-but- ¹H NMR (400 MHz, DMSO-d₆) δ 12.06 (s, 409 2-enyl]-7-oxo-1H- 1H), 7.98 (t, J = 5.7 Hz, 1H), 7.73 (s, 1H), pyrrolo[2,3-c]pyridine-4- 7.38-7.25 (m, 7H), 6.75-6.69 (m, 1H), carbonyl]amino]ethyl]carbamate 5.67-5.59 (m, 2H), 5.02 (s, 2H), 4.57-4.50 (m, 2H), 3.32-3.27 (m, 2H), 3.23-3.14 (m, 2H), 1.68-1.62 (m, 3H). 14 N-(2-acetamidoethyl)-6- ¹H NMR (400 MHz, DMSO-d₆) δ 12.07 (s, 317 but-2-enyl-7-oxo-1H- 1H), 8.05-7.91 (m, 2H), 7.73 (s, 1H), pyrrolo[2,3-c]pyridine-4- 7.39-7.31 (m, 1H), 6.81-6.65 (m, 1H), carboxamide 5.81-5.50 (m, 2H), 4.64-4.46 (m, 3H), 3.36-3.27 (m, 2H), 3.25-3.13 (m, 2H), 1.81 (s, 3H), 1.72-1.55 (m, 4H). 15 6-but-2-enyl-N-tert- ¹H NMR (400 MHz, DMSO-d₆) δ 12.03 (s, 288 butyl-7-oxo-1H- 1H), 7.68 (s, 1H), 7.43-7.15 (m, 2H), pyrrolo[2,3-c]pyridine-4- 6.63 (d, J = 2.7 Hz, 1H), 5.70-5.44 (m, 2H), carboxamide 4.54 (dd, J = 3.9, 2.0 Hz, 2H), 1.73-1.59 (m, 3H), 1.38 (s, 10H). 16 N-[2-(4-benzylpiperazin- ¹H NMR (400 MHz, DMSO-d₆) δ 12.10 (s, 434 1-yl)ethyl]-6-but-2-enyl- 1H), 7.73 (d, J = 18.6 Hz, 2H), 7.38-7.19 (m, 7-oxo-1H-pyrrolo[2,3- 7H), 6.70 (d, J = 2.8 Hz, 1H), 5.69-5.59 (m, c]pyridine-4- 2H), 4.58-4.52 (m, 2H), 3.45 (s, 2H), carboxamide 3.40-3.31 (m, 2H), 2.58-2.28 (m, 10H), 1.69-1.62 (m, 3H). 17 benzyl N-[3-[(6-but-2- ¹H NMR (400 MHz, DMSO-d₆) δ 12.07 (s, 423 enyl-7-oxo-1H- 1H), 7.91 (t, J = 5.7 Hz, 1H), 7.72 (s, 1H), pyrrolo[2,3-c]pyridine-4- 7.41-7.22 (m, 7H), 6.71 (d, J = 2.8 Hz, 1H), carbonyl)amino]propyl]carbamate 5.71-5.59 (m, 2H), 5.02 (s, 2H), 4.55 (d, J = 4.9 Hz, 2H), 3.31-3.21 (m, 2H), 3.12-3.02 (m, 2H), 1.72-1.61 (m, 5H). 18 6-but-2-enyl-N-(1- ¹H NMR (400 MHz, DMSO-d₆) δ 12.06 (s, 328 methylcyclohexyl)-7- 1H), 7.66 (s, 1H), 7.34 (d, J = 2.7 Hz, 1H), oxo-1H-pyrrolo[2,3- 6.99 (s, 1H), 6.60 (d, J = 2.7 Hz, 1H), c]pyridine-4- 5.78-5.52 (m, 2H), 4.62-4.49 (m, 2H), carboxamide 2.28-2.11 (m, 2H), 1.72-1.62 (m, 3H), 1.56-1.44 (m, 4H), 1.44-1.17 (m, 7H). 19 benzyl 3-[2-[(6-but-2- ¹H NMR (400 MHz, DMSO-d₆) δ 12.06 (s, 463 enyl-7-oxo-1H- 1H), 7.96 (s, 1H), 7.71 (d, J = 3.0 Hz, 1H), pyrrolo[2,3-c]pyridine-4- 7.50-7.18 (m, 7H), 6.71 (d, J = 2.7 Hz, 1H), carbonyl)amino]ethyl]pyrrolidine- 5.74-5.53 (m, 2H), 5.06 (s, 2H), 4.54 (s, 2H), 1-carboxylate 3.69-3.51 (m, 1H), 3.52-3.36 (m, 1H), 3.32-3.14 (m, 2H), 3.00-2.84 (m, 1H), 2.27-2.13 (m, 1H), 2.13-1.97 (m, 1H), 1.70-1.40 (m, 7H). 20 6-methyl-7-oxo-N-[2-[1- 1H NMR (400 MHz, DMSO-d6) δ 12.07 (s, 385 (2,2,2-trifluoroethyl)-4- 1H), 7.90 (t, J = 5.6 Hz, 1H), 7.79 (s, 1H), piperidyl]ethyl]-1H- 7.31 (t, J = 2.5 Hz, 1H), 6.69 (dd, J = 2.9, 1.5 Hz, pyrrolo[2,3-c]pyridine-4- 1H), 3.55 (s, 3H), 3.32-3.22 (m, 2H), carboxamide 3.11 (q, J = 10.3 Hz, 2H), 2.89 (dt, J = 12.0, 3.4 Hz, 2H), 2.28 (dd, J = 12.8, 10.1 Hz, 2H), 1.66 (dd, J = 11.8, 3.6 Hz, 2H), 1.45 (q, J = 7.1 Hz, 2H), 1.35-1.24 (m, 1H), 1.17 (qd, J = 11.9, 3.8 Hz, 2H). 21 N-[4- ¹H NMR (400 MHz, DMSO-d₆) δ 12.02 (s, 317 (dimethylamino)cyclohexyl]- 1H), 7.86-7.76 (m, 1H), 7.75-7.63 (m, 1H), 6-methyl-7-oxo-1H- 7.30 (d, J = 2.7 Hz, 1H), 6.68 (d, J = 2.7 Hz, pyrrolo[2,3-c]pyridine-4- 1H), 3.95-3.62 (m, 1H), 3.54 (s, 3H), 2.17 (s, carboxamide 6H), 2.14-1.97 (m, 1H), 1.95-1.87 (m, 1H), 1.86-1.67 (m, 3H), 1.59-1.42 (m, 2H), 1.36-1.21 (m, 2H). 22 N-(1-benzylpyrrolidin-3- ¹H NMR (400 MHz, DMSO-d₆) δ 12.11 (s, 365 yl)-N,6-dimethyl-7-oxo- 1H), 7.36-7.27 (m, 6H), 7.27-7.19 (m, 1H), 1H-pyrrolo[2,3- 6.19-6.13 (m, 1H), 4.69 (s, 1H), 3.60 (d, J = 13.1 Hz, c]pyridine-4- 1H), 3.54-3.44 (m, 4H), 2.94 (s, carboxamide 3H), 2.82-2.71 (m, 1H), 2.71-2.63 (m, 1H), 2.42 (t, J = 9.2 Hz, 1H), 2.22 (q, J = 8.2 Hz, 1H), 2.07-1.99 (m, 1H), 1.90-1.76 (m, 1H). 23 N-[(1- ¹H NMR (400 MHz, DMSO-d₆) δ 12.10 (s, 331 isopropylpyrrolidin-3- 1H), 7.39 (s, 1H), 7.32 (d, J = 2.8 Hz, 1H), yl)methyl]-N,6-dimethyl- 6.18 (d, J = 2.8 Hz, 1H), 3.53 (s, 3H), 7-oxo-1H-pyrrolo[2,3- 3.44-3.36 (m, 2H), 2.94 (s, 3H), 2.47-2.34 (m, c]pyridine-4- 3H), 2.29-2.16 (m, 2H), 1.87-1.75 (m, 1H), carboxamide 1.36-1.25 (m, 1H), 1.02-0.90 (m, 7H). 24 6-methyl-N-[(1-methyl- ¹H NMR (400 MHz, DMSO-d₆) δ 12.04 (s, 303 3-piperidyl)methyl]-7- 1H), 7.93 (t, J = 5.8 Hz, 1H), 7.82 (s, 1H), oxo-1H-pyrrolo[2,3- 7.34-7.28 (m, 1H), 6.73-6.67 (m, 1H), c]pyridine-4- 3.55 (s, 3H), 3.21-3.04 (m, 2H), 2.76-2.67 (m, carboxamide 1H), 2.65-2.57 (m, 1H), 2.13 (s, 3H), 1.88-1.74 (m, 2H), 1.71-1.57 (m, 3H), 1.50-1.37 (m, 1H), 0.98-0.85 (m, 1H). 25 6-methyl-N-[2-(1- ¹H NMR (400 MHz, DMSO-d₆) δ 12.05 (s, 317 methyl-4- 1H), 7.88 (t, J = 5.6 Hz, 1H), 7.78 (s, 1H), piperidyl)ethyl]-7-oxo- 7.31 (t, J = 2.7 Hz, 1H), 6.69 (t, J = 2.3 Hz, 1H-pyrrolo[2,3- 1H), 3.55 (s, 3H), 3.32-3.22 (m, 2H), c]pyridine-4- 2.76-2.67 (m, 2H), 2.12 (s, 3H), 1.85-1.74 (m, carboxamide 2H), 1.70-1.61 (m, 2H), 1.50-1.40 (m, 2H), 1.33-1.08 (m, 3H). 26 6-methyl-N-[2-(4- ¹H NMR (400 MHz, DMSO-d₆) δ 12.09 (s, 317 methyl-1- 1H), 7.80 (s, 1H), 7.75 (t, J = 5.6 Hz, 1H), piperidyl)ethyl]-7-oxo- 7.34 (t, J = 2.6 Hz, 1H), 6.73-6.67 (m, 1H), 1H-pyrrolo[2,3- 3.55 (s, 3H), 3.40-3.30 (m, 2H), c]pyridine-4- 2.90-2.81 (m, 2H), 2.44 (t, J = 6.9 Hz, 2H), carboxamide 2.00-1.88 (m, 2H), 1.62-1.53 (m, 2H), 1.39-1.27 (m, 1H), 1.20-1.06 (m, 2H), 0.89 (d, J = 6.4 Hz, 3H). 27 N-[(1-ethylpyrrolidin-3- ¹H NMR (400 MHz, DMSO-d₆) δ 12.11 (s, 317 yl)methyl]-N,6-dimethyl- 1H), 7.39 (s, 1H), 7.32 (d, J = 2.8 Hz, 1H), 7-oxo-1H-pyirolo[2,3- 6.18 (d, J = 2.7 Hz, 1H), 3.53 (s, 3H), c]pyridine-4- 3.43-3.36 (m, 2H), 2.94 (s, 3H), 2.41-2.29 (m, carboxamide 1H), 2.19 (s, 1H), 1.83 (s, 1H), 1.31 (s, 1H), 1.03-0.90 (m, 4H). 28 6-methyl-4-(7-methyl- ¹H NMR (400 MHz, DMSO-d₆) δ 12.06 (s, 301 2,7- 1H), 7.58 (s, 1H), 7.31 (d, J = 2.7 Hz, 1H), diazaspiro[3.4]octane-2- 6.55 (d, J = 2.7 Hz, 1H), 4.06 (s, 4H), 3.55 (s, carbonyl)-1H- 3H), 2.63 (s, 2H), 2.44 (t, J = 7.1 Hz, 2H), pyrrolo[2,3-c]pyridin-7- 2.22 (s, 3H), 2.02 (t, J = 7.1 Hz, 2H). one 29 6-methyl-N-[3-(2- ¹H NMR (400 MHz, DMSO-d₆) δ 12.06 (s, 331 methyl-1- 1H), 7.94 (t, J = 5.6 Hz, 1H), 7.78 (s, 1H), piperidyl)propyl]-7-oxo- 7.32 (d, 1H), 6.69 (d, J = 2.7 Hz, 1H), 3.55 (s, 1H-pyrrolo[2,3- 3H), 3.30-3.19 (m, 2H), 2.83-2.62 (m, 2H), c]pyridine-4- 2.31-2.19 (m, 2H), 2.10-1.99 (m, 1H), carboxamide 1.70-1.46 (m, 5H), 1.46-1.31 (m, 1H), 1.30-1.10 (m, 2H), 0.98 (d, J = 6.2 Hz, 3H). 30 N-[2-(4-hydroxy-1- ¹H NMR (400 MHz, DMSO-d₆) δ 12.09 (s, 319 piperidyl)ethyl]-6- 1H), 7.79 (s, 1H), 7.75 (t, J = 5.5 Hz, 1H), methyl-7-oxo-1H- 7.34 (d, J = 2.8 Hz, 1H), 6.70 (d, J = 2.8 Hz, pyrrolo[2,3-c]pyridine-4- 1H), 4.51 (d, J = 4.1 Hz, 1H), 3.55 (s, 3H), carboxamide 3.49-3.38 (m, 1H), 3.38-3.30 (m, 2H), 2.80-2.70 (m, 2H), 2.44 (t, J = 6.9 Hz, 2H), 2.13-2.02 (m, 2H), 1.76-1.65 (m, 2H), 1.46-1.32 (m, 2H). 31 6-methyl-N-(3- ¹H NMR (400 MHz, DMSO-d₆) δ 12.06 (s, 319 morpholinopropyl)-7- 1H), 7.94 (t, J = 5.5 Hz, 1H), 7.79 (s, 1H), oxo-1H-pyrrolo[2,3- 7.32 (d, J = 2.7 Hz, 1H), 6.70 (d, J = 2.7 Hz, c]pyridine-4- 1H), 3.59-3.52 (m, 7H), 3.31-3.23 (m, 2H), carboxamide 2.39-2.29 (m, 6H), 1.68 (p, J = 7.1 Hz, 2H). 32 6-methyl-N-[2-(4- ¹H NMR (400 MHz, DMSO-d₆) δ 12.09 (s, 318 methylpiperazin-1- 1H), 7.79 (s, 1H), 7.76 (t, J = 5.5 Hz, 1H), yl)ethyl]-7-oxo-1H- 7.34 (d, J = 2.7 Hz, 1H), 6.71 (d, J = 2.8 Hz, pyrrolo[2,3-c]pyridine-4- 1H), 3.55 (s, 3H), 3.41-3.32 (m, 2H), carboxamide 2.49-2.42 (m, 3H), 2.32 (s, 6H), 2.15 (s, 3H). 33 N-[2-(3.5-dimethyl-1- ¹H NMR (400 MHz, DMSO-d₆) δ 12.09 (s, 331 piperidyl)ethyl]-6- 1H), 7.79 (s, 1H), 7.75 (t, J = 5.5 Hz, 1H), methyl-7-oxo-1H- 7.34 (d, J = 2.8 Hz, 1H), 6.69 (d, J = 2.7 Hz, pyrrolo[2,3-c]pyridine-4- 1H), 3.55 (s, 3H), 3.36 (q, J = 6.5 Hz, 2H), carboxamide 2.88-2.80 (m, 2H), 2.44 (t, J = 6.9 Hz, 2H), 1.71-1.52 (m, 3H), 1.46 (t, J = 10.8 Hz, 2H), 0.82 (d, J = 6.4 Hz, 6H), 0.49 (q, J = 11.7 Hz, 1H). 34 6-methyl-N-[3-(4- ¹H NMR (400 MHz, DMSO-d₆) δ 12.06 (s, 332 methylpiperazin-1- 1H), 7.94 (t, J = 5.5 Hz, 1H), 7.79 (s, 1H), yl)propyl]-7-oxo-1H- 7.32 (d, J = 2.8 Hz, 1H), 6.69 (d, J = 2.7 Hz, pyrrolo[2,3-c]pyridine-4- 1H), 3.55 (s, 3H), 3.31-3.22 (m, 2H), carboxamide 2.38-2.26 (m, 10H), 2.12 (s, 3H), 1.66 (p, J = 7.0 Hz, 2H). 35 N-(1,1-dimethyl-2- ¹H NMR (400 MHz, DMSO-d₆) δ 12.09 (s, 333 morpholino-ethyl)-6- 1H), 7.74 (s, 1H), 7.37-7.31 (m, 1H), 7.22 (s, methyl-7-oxo-1H- 1H), 6.65 (d, J = 2.7 Hz, 1H), 3.59-3.51 (m, pyrrolo[2,3-c]pyridine-4- 7H), 2.62 (s, 2H), 2.55-2.49 (m, 2H), 1.36 (s, carboxamide 6H). 36 6-methyl-N-(2-methyl-2- ¹H NMR (400 MHz, DMSO-d₆) δ 12.20 (s, 333 morpholino-propyl)-7- 1H), 7.81 (s, 1H), 7.42 (d, J = 2.8 Hz, 1H), oxo-1H-pyrrolo [2,3- 7.34 (t, J = 5.5 Hz, 1H), 6.72 (d, J = 2.8 Hz, c]pyridine-4- 1H), 3.58 (d, J = 5.9 Hz, 7H), 3.31 (s, 1H), carboxamide 2.53 (t, J = 4.5 Hz, 4H), 1.02 (s, 6H). 37 N-[2-(1,1-dioxo-1,4- ¹H NMR (400 MHz, DMSO-d₆) δ 12.08 (s, 353 thiazinan-4-yl)ethyl]-6- 1H), 7.85 (t, J = 5.7 Hz, 1H), 7.79 (s, 1H), methyl-7-oxo-1H- 7.33 (d, J = 2.8 Hz, 1H), 6.70 (d, J = 2.7 Hz, pyrrolo[2,3-c]pyridine-4- 1H), 3.55 (s, 3H), 3.37 (q, J = 6.3 Hz, 2H), carboxamide 3.12-3.04 (m, 4H), 3.01-2.94 (m, 4H), 2.67 (t, J = 6.6 Hz, 2H). 38 6-methyl-4-(4- ¹H NMR (400 MHz, DMSO-d₆) δ 12.13 (s, 275 methylpiperazine-1- 1H), 7.42 (s, 1H), 7.33 (d, J = 2.8 Hz, 1H), carbonyl)-1H- 6.26 (d, J = 2.8 Hz, 1H), 3.53 (s, 3H), pyrrolo[2,3-c]pyridin-7- 3.51-3.44 (m, 4H), 2.30 (t, J = 5.0 Hz, 4H), 2.19 (s, one 3H). 39 N,6-dimethyl-N-(1- ¹H NMR (400 MHz, DMSO-d₆) δ 12.11 (s, 303 methyl-4-piperidyl)-7- 1H), 7.36 (s, 1H), 7.31 (d, J = 2.6 Hz, 1H), oxo-1H-pyrrolo[2,3- 6.18 (d, J = 2.7 Hz, 1H), 3.95 (s, 1H), 3.52 (s, c]pyridine-4- 3H), 2.84-2.76 (m, 5H), 2.12 (s, 3H), carboxamide 1.85-1.73 (m, 4H), 1.61-1.54 (m, 2H). 40 4-[4- ¹H NMR (400 MHz, DMSO-d₆) δ 12.12 (s, 303 (dimethylamino)piperidine- 1H), 7.41 (s, 1H), 7.33 (d, J = 2.8 Hz, 1H), 1-carbonyl]-6-methyl- 6.24 (d, J = 2.8 Hz, 1H), 4.04 (s, 2H), 3.53 (s, 1H-pyrrolo[2,3- 3H), 2.97-2.86 (m, 2H), 2.36-2.24 (m, 1H), c]pyridin-7-one 2.16 (s, 6H), 1.75 (d, J = 12.2 Hz, 2H), 1.38-1.23 (m, 2H). 41 N-(1-isopropyl-4- ¹H NMR (400 MHz, DMSO-d₆) δ 12.11 (s, 331 piperidyl)-N,6-dimethyl- 1H), 7.36 (s, 1H), 7.32 (t, J = 2.7 Hz, 1H), 7-oxo-1H-pyrrolo[2,3- 6.21-6.15 (m, 1H), 3.93 (s, 1H), 3.52 (s, 3H), c]pyridine-4- 2.85-2.77 (m, 5H), 2.66 (p, J = 6.6 Hz, 1H), carboxamide 2.10-2.02 (m, 2H), 1.81-1.66 (m, 2H), 1.65-1.57 (m, 2H), 0.92 (d, J = 6.5 Hz, 6H). 42 6-methyl-7-oxo-N-[1-(2- ¹H NMR (400 MHz, DMSO-d₆) δ 12.03 (s, 352 pyridyl)-4-piperidyl]-1H- 1H), 8.14-8.07 (m, 1H), 7.84-7.77 (m, 2H), pyrrolo[2,3-c]pyridine-4- 7.57-7.47 (m, 1H), 7.30 (t, J = 2.7 Hz, 1H), carboxamide 6.87 (d, J = 8.6 Hz, 1H), 6.70 (t, J = 2.4 Hz, 1H), 6.64-6.56 (m, 1H), 4.33-4.24 (m, 2H), 4.13-3.98 (m, 1H), 3.54 (s, 3H), 3.02-2.89 (m, 2H), 1.91-1.82 (m, 2H), 1.59-1.44 (m, 2H). 43 N-(1-cyclopentyl-4- ¹H NMR (400 MHz, DMSO-d₆) δ 12.04 (s, 343 piperidyl)-6-methyl-7- 1H), 7.80 (s, 1H), 7.30 (t, J = 2.8 Hz, 1H), oxo-1H-pyrrolo[2,3- 6.68 (t, J = 2.4 Hz, 1H), 3.72 (s, 1H), 3.55 (s, c]pyridine-4- 3H), 3.28 (s, 2H), 2.98-2.93 (m, 2H), carboxamide 1.84-1.79 (m, 4H), 1.63-1.58 (m, 2H), 1.56-1.46 (m, 3H), 1.38-1.33 (m, 2H). 44 6-methyl-7-oxo-N-(1- ¹H NMR (400 MHz, DMSO-d₆) δ 12.04 (s, 353 pyrimidin-2-yl-4- 1H), 8.36 (d, J = 4.7 Hz, 2H), 7.84-7.77 (m, piperidyl)-1H- 2H), 7.30 (t, J = 2.7 Hz, 1H), 6.70 (t, J = 2.4 Hz, pyrrolo[2,3-c]pyridine-4- 1H), 6.60 (t, J = 4.7 Hz, 1H), carboxamide 4.67-4.57 (m, 2H), 4.16-4.01 (m, 1H), 3.54 (s, 3H), 3.12-3.00 (m, 2H), 1.93-1.84 (m, 2H), 1.54-1.39 (m, 2H). 45 6-methyl-N-[2-(3- ¹H NMR (400 MHz, DMSO-d₆) δ 12.09 (s, 317 methyl-1- 1H), 7.79 (s, 1H), 7.74 (t, J = 5.5 Hz, 1H), piperidyl)ethyl]-7-oxo- 7.34 (d, J = 2.8 Hz, 1H), 6.70 (d, J = 2.8 Hz, 1H-pyrrolo[2,3- 1H), 3.55 (s, 3H), 3.41-3.31 (m, 2H), c]pyridine-4- 2.85-2.76 (m, 2H), 2.43 (t, J = 6.9 Hz, 2H), carboxamide 1.94-1.83 (m, 1H), 1.69-1.38 (m, 6H), 0.84 (d, J = 6.1 Hz, 3H). 46 6-methyl-4-[4-(3- ¹H NMR (400 MHz, DMSO-d₆) δ 12.14 (s, 351.18 pyridylmethyl)piperidine- 1H), 8.50-8.34 (m, 2H), 7.64-7.55 (m, 1H), 1-carbonyl]-1H- 7.39 (s, 1H), 7.37-7.25 (m, 2H), 6.24 (d, J = 2.8 Hz, pyrrolo[2,3-c]pyridin-7- 1H), 4.32-3.84 (m, 2H), 3.53 (s, 3H), one 2.85 (t, J = 12.2 Hz, 2H), 2.55 (d, J = 7.1 Hz, 2H), 1.87-1.70 (m, 1H), 1.57 (d, J = 12.8 Hz, 2H), 1.23-1.03 (m, 2H). 47 4-(4-tert-butylpiperidine- ¹H NMR (400 MHz, DMSO-d₆) δ 7.39 (s, 316.2 1-carbonyl)-6-methyl- 1H), 7.32 (d, J = 2.7 Hz, 1H), 6.21 (d, J = 2.7 Hz, 1H-pyrrolo[2,3- 1H), 4.11 (d, J = 16.3 Hz, 2H), 3.52 (s, c]pyridin-7-one 3H), 2.90-2.82 (m, 2H), 1.81-1.58 (m, 2H), 1.33-1.17 (m, 1H), 1.17-1.01 (m, 2H), 0.84 (s, 9H), 0.81 (d, J = 2.8 Hz, 1H). 48 4-[4-(4- ¹H NMR (400 MHz, DMSO-d₆) δ 12.15 (s, 370.13 chlorophenyl)piperidine- 1H), 7.46 (s, 1H), 7.39-7.27 (m, 5H), 1-carbonyl]-6-methyl- 6.35-6.28 (m, 1H), 4.19 (s, 2H), 3.54 (s, 3H), 1H-pyrrolo[2,3- 3.00 (t, J = 12.7 Hz, 2H), 2.88-2.75 (m, 1H), c]pyridin-7-one 1.78 (d, J = 12.7 Hz, 2H), 1.64-1.48 (m, 2H). 49 4-[4-(3- ¹H NMR (400 MHz, DMSO-d₆) δ 12.15 (s, 354.16 fluorophenyl)piperidine- 1H), 7.46 (s, 1H), 7.40-7.29 (m, 2H), 1-carbonyl]-6-methyl- 7.17-7.10 (m, 2H), 7.07-6.98 (m, 1H), 6.34 (d, J = 2.8 Hz, 1H-pyrrolo[2,3- 1H), 4.20 (s, 2H), 3.54 (s, 3H), c]pyridin-7-one 3.08-2.93 (m, 2H), 2.89 (t, J = 5.6 Hz, 1H), 1.80 (d, J = 13.2 Hz, 2H), 1.68-1.51 (m, 2H). 50 4-[4-(benzimidazol-1- ¹H NMR (400 MHz, DMSO-d₆) δ 12.18 (s, 376.18 yl)piperidine-1- 1H), 8.39 (s, 1H), 7.74-7.61 (m, 2H), 7.50 (s, carbonyl]-6-methyl-1H- 1H), 7.36 (d, J = 2.8 Hz, 1H), 7.32-7.16 (m, pyrrolo[2,3-c]pyridin-7- 2H), 6.39 (d, J = 2.8 Hz, 1H), 4.77-4.63 (m, one 1H), 4.29 (d, J = 15.4 Hz, 2H), 3.56 (s, 3H), 3.17 (t, J = 12.7 Hz, 2H), 2.20-1.89 (m, 4H). 51 6-methyl-4-(4-pyrazin-2- ¹H NMR (400 MHz, DMSO-d₆) δ 12.15 (s, 338.16 ylpiperidine-1-carbonyl)- 1H), 8.64 (d, J = 1.5 Hz, 1H), 8.61-8.56 (m, 1H-pyrrolo[2,3- 1H), 8.50 (d, J = 2.5 Hz, 1H), 7.46 (s, 1H), c]pyridin-7-one 7.35 (t, J = 2.6 Hz, 1H), 6.33-6.28 (m, 1H), 4.20 (s, 2H), 3.54 (s, 3H), 3.15-2.99 (m, 3H), 1.89 (d, J = 12.8 Hz, 2H), 1.79-1.60 (m, 2H). 52 4-[4- ¹H NMR (400 MHz, DMSO-d₆) δ 12.14 (s, 371.24 [cyclohexyl(methyl)amino]piperidine- 1H), 7.42 (s, 1H), 7.38-7.29 (m, 1H), 1-carbonyl]- 6.24 (d, J = 2.8 Hz, 1H), 4.27-3.88 (m, 2H), 6-methyl-1H- 3.53 (d, J = 2.2 Hz, 3H), 2.95-2.84 (m, 2H), pyrrolo[2,3-c]pyridin-7- 2.75-2.65 (m, 1H), 2.14 (d, J = 5.0 Hz, 3H), one 1.69 (d, J = 18.6 Hz, 6H), 1.55 (d, J = 12.3 Hz, 2H), 1.44-1.31 (m, 1H), 1.30-1.12 (m, 4H), 1.05 (s, 2H). 53 4-(4-fluoropiperidine-1- ¹H NMR (400 MHz, DMSO-d₆) δ 12.21 (d, J = 46.1 Hz, 278.13 carbonyl)-6-methyl-1H- 1H), 7.56-7.18 (m, 2H), 6.28 (d, J = 2.8 Hz, pyrrolo[2,3-c]pyridin-7- 1H), 5.07-4.68 (m, 1H), 3.59 (d, J = 9.9 Hz, one 2H), 3.53 (s, 3H), 3.51-3.43 (m, 2H), 1.98-1.78 (m, 2H), 1.78-1.60 (m, 2H). 54 N-[2-[1-(6-methyl-7-oxo- ¹H NMR (400 MHz, DMSO-d₆) δ 7.39 (s, 381.16 1H-pyrrolo[2,3- 1H), 7.33 (d, J = 2.8 Hz, 1H), 6.25 (d, J = 2.7 Hz, c]pyridine-4-carbonyl)-4- 1H), 4.06 (s, 2H), 3.53 (s, 3H), piperidyl]ethyl]methanesulfonamide 3.15-3.05 (m, 1H), 3.03-2.92 (m, 4H), 1.80-1.58 (m, 5H), 1.48-1.37 (m, 3H), 1.13-1.02 (m, 2H). 55 6-methyl-4-[4-(2- ¹H NMR (400 MHz, DMSO-d₆) δ 12.15 (s, 337.17 pyridyl)piperidine-1- 1H), 8.55-8.46 (m, 1H), 7.77-7.68 (m, 1H), carbonyl]-1H- 7.46 (d, J = 1.2 Hz, 1H), 7.37-7.26 (m, 2H), pyrrolo[2,3-c]pyridin-7- 7.26-7.19 (m, 1H), 6.32-6.28 (m, 1H), one 4.18 (s, 2H), 3.54 (d, J = 1.2 Hz, 3H), 3.11-2.92 (m, 3H), 1.92-1.79 (m, 2H), 1.77-1.61 (m, 2H). 56 6-methyl-4-(4-pyrimidin- ¹H NMR (400 MHz, DMSO-d₆) δ 12.16 (s, 338.16 4-ylpiperidine-1- 1H), 9.21-9.00 (m, 1H), 8.86-8.61 (m, 1H), carbonyl)-1H- 7.51-7.44 (m, 2H), 7.35 (d, J = 2.7 Hz, 1H), pyrrolo[2,3-c]pyridin-7- 6.29 (d, J = 2.7 Hz, 1H), 4.19 (s, 2H), 3.54 (s, one 2H), 3.11-2.92 (m, 3H), 2.92-2.82 (m, 1H), 1.96-1.83 (m, 2H), 1.77-1.59 (m, 2H). 57 6-methyl-4-[4- ¹H NMR (400 MHz, DMSO-d₆) δ 12.16 (s, 328.13 (trifluoromethyl)piperidine- 1H), 7.47 (s, 1H), 7.34 (d, J = 2.8 Hz, 1H), 1-carbonyl]-1H- 6.25 (d, J = 2.8 Hz, 1H), 4.15 (s, 2H), 3.53 (s, pyrrolo[2,3-c]pyridin-7- 3H), 2.95 (t, J = 13.2 Hz, 2H), 2.70-2.57 (m, one 1H), 1.84 (d, J = 12.5 Hz, 2H), 1.48-1.29 (m, 2H). 58 6-methyl-4-[4-(2- ¹H NMR (400 MHz, DMSO-d₆) δ 12.14 (s, 351.2 pyridylmethyl)piperidine- 1H), 8.52-8.43 (m, 1H), 7.73-7.62 (m, 1H), 1-carbonyl]-1H- 7.39 (s, 1H), 7.33 (d, J = 2.8 Hz, 1H), pyrrolo[2,3-c]pyridin-7- 7.27-7.13 (m, 2H), 6.24 (d, J = 2.7 Hz, 1H), 4.02 (s, one 2H), 3.52 (s, 3H), 2.88 (d, J = 12.3 Hz, 2H), 2.68 (d, J = 7.1 Hz, 2H), 2.43-2.30 (m, 0H), 2.15-1.88 (m, 1H), 1.57 (d, J = 12.8 Hz, 2H), 1.27-1.09 (m, 2H). 59 6-methyl-4-[4-(1- ¹H NMR (400 MHz, DMSO-d₆) δ 12.13 (s, 343.2 piperidyl)piperidine-1- 1H), 7.41 (s, 1H), 7.35-7.31 (m, 1H), carbonyl]-1H- 6.24 (d, J = 2.7 Hz, 1H), 4.06 (s, 2H), 3.53 (s, 3H), pyrrolo[2,3-c]pyridin-7- 2.85 (d, J = 11.6 Hz, 2H), 2.46-2.36 (m, 5H), one 1.72 (d, J = 12.3 Hz, 2H), 1.47 (t, J = 5.5 Hz, 4H), 1.41-1.32 (m, 4H). 60 4-[3- ¹H NMR (400 MHz, DMSO-d₆) δ 12.10 (s, 289.2 (dimethylamino)pyrrolidine- 1H), 7.52 (s, 1H), 7.31 (d, J = 2.8 Hz, 1H), 1-carbonyl]-6-methyl- 6.33 (d, J = 2.7 Hz, 1H), 3.53 (s, 3H), 3.33 (s, 1H-pyrrolo[2,3- 1H), 2.87 (s, 3H), 2.77-2.55 (m, 1H), c]pyridin-7-one 2.17-1.95 (m, 7H), 1.89-1.65 (m, 1H). 61 6-methyl-4-[4-(4- ¹H NMR (400 MHz, DMSO-d₆) δ 12.13 (s, 358.2 methylpiperazin-1- 1H), 7.41 (s, 1H), 7.33 (d, J = 2.8 Hz, 1H), yl)piperidine-1- 6.24 (d, J = 2.8 Hz, 1H), 4.05 (s, 2H), 3.53 (s, carbonyl]-1H- 4H), 2.97-2.80 (m, 4H), 2.35-2.18 (m, 4H), pyrrolo[2,3-c]pyridin-7- 2.13 (d, J = 4.6 Hz, 5H), 1.81-1.70 (m, 2H), one 1.42-1.23 (m, 2H). 62 6-methyl-4-[4-(4-methyl- ¹H NMR (400 MHz, DMSO-d₆) δ 12.15 (s, 357.2 1-piperidyl)piperidine-1- 1H), 7.40 (s, 1H), 7.32 (d, J = 2.8 Hz, 1H), carbonyl]-1H- 6.23 (d, J = 2.8 Hz, 1H), 3.52 (s, 3H), pyrrolo[2,3-c]pyridin-7- 3.00-2.72 (m, 6H), 2.49-2.39 (m, 2H), one 2.17-2.01 (m, 2H), 1.86-1.64 (m, 2H), 1.64-1.50 (m, 2H), 1.47-1.17 (m, 2H), 1.17-0.96 (m, 2H), 0.96-0.79 (m, 3H). 63 6-methyl-4-(4- ¹H NMR (400 MHz, DMSO-d₆) δ 12.14 (s, 345.2 morpholinopiperidine-1- 1H), 7.42 (s, 1H), 7.33 (d, J = 2.8 Hz, 1H), carbonyl)-1H- 2.47-2.46 (m, 0H), 6.25 (d, J = 2.7 Hz, 1H), pyrrolo[2,3-c]pyridin-7- 4.08 (d, J = 16.5 Hz, 2H), 3.54 (d, J = 11.3 Hz, one 8H), 3.01-2.81 (m, 3H), 2.45 (d, J = 4.7 Hz, 3H), 1.79 (d, J = 12.5 Hz, 2H), 1.32 (q, J = 14.3, 12.7 Hz, 2H). 64 1-(6-methyl-7-oxo-1H- ¹H NMR (400 MHz, DMSO-d₆) δ 12.16 (s, 285.2 pyrrolo[2,3-c]pyridine-4- 1H), 7.45 (s, 1H), 7.34 (d, J = 2.1 Hz, 1H), carbonyl)piperidine-4- 6.29 (d, J = 2.7 Hz, 1H), 3.70 (s, 2H), 3.53 (s, carbonitrile 3H), 3.32 (s, 2H), 3.13 (m, J = 8.7, 4.5 Hz, 1H), 1.97-1.83 (m, 2H), 1.71 (m, J = 13.7, 9.2, 4.5 Hz, 2H). 65 6-methyl-4-(4- ¹H NMR (400 MHz, DMSO-d₆) δ 7.38 (s, 274.2 methylpiperidine-1- 1H), 7.32 (d, J = 2.7 Hz, 1H), 6.23 (d, J = 2.7 Hz, carbonyl)-1H- 1H), 3.52 (s, 3H), 2.95-2.82 (m, 4H), pyrrolo[2,3-c]pyridin-7- 1.72-1.54 (m, 4H), 1.12-0.98 (m, 2H), one 0.91 (d, J = 6.0 Hz, 3H). 66 4-(4-methoxypiperidine- ¹H NMR (400 MHz, DMSO-d₆) δ 12.14 (s, 290.2 1-carbonyl)-6-methyl- 1H), 7.42 (s, 1H), 7.36-7.30 (m, 1H), 1H-pyrrolo[2,3- 6.25 (d, J = 2.7 Hz, 1H), 3.71 (d, J = 10.6 Hz, 2H), c]pyridin-7-one 3.53 (s, 3H), 3.47-3.36 (m, 1H), 3.25 (s, 3H), 3.25-3.17 (m, 2H), 1.88-1.78 (m, 2H), 1.48-1.34 (m, 2H). 67 6-methyl-4-[4-(3-methyl- ¹H NMR (400 MHz, DMSO-d₆) δ 7.40 (s, 357.2 1-piperidyl)piperidine-1- 1H), 7.32 (d, J = 2.7 Hz, 1H), 6.23 (d, J = 2.7 Hz, carbonyl]-1H- 1H), 4.06 (s, 2H), 3.52 (s, 3H), 2.86 (d, J = 4.2 Hz, pyrrolo[2,3-c]pyridin-7- 2H), 2.80-2.69 (m, 3H), one 2.12-1.95 (m, 2H), 1.84-1.67 (m, 4H), 1.44-1.29 (m, 4H), 0.89-0.76 (m, 5H). 68 4-[4-(1-hydroxy-1- ¹H NMR (400 MHz, DMSO-d₆) δ 12.14 (s, 318.2 methyl-ethyl)piperidine- 1H), 7.40 (s, 1H), 7.33 (d, J = 2.7 Hz, 1H), 1-carbonyl]-6-methyl- 6.23 (d, J = 2.8 Hz, 1H), 4.14 (s, 2H), 3.53 (s, 1H-pyrrolo[2,3- 3H), 2.95-2.85 (m, 1H), 2.84-2.71 (m, 2H), c]pyridin-7-one 1.81-1.61 (m, 2H), 1.50-1.34 (m, 1H), 1.22-1.08 (m, 2H), 1.03 (s, 6H). 69 4-[4-[(4- ¹H NMR (400 MHz, DMSO-d₆) δ 12.14 (s, 368.2 fluorophenyl)methyl]piperidine- 1H), 7.39 (s, 1H), 7.33 (d, J = 2.8 Hz, 1H), 1-carbonyl]-6- 7.20 (m, J = 9.1, 5.7, 2.8 Hz, 2H), methyl-1H-pyrrolo[2,3- 7.14-7.04 (m, 2H), 6.24 (d, J = 2.7 Hz, 1H), 4.02 (s, c]pyridin-7-one 2H), 3.52 (s, 3H), 2.84 (t, J = 12.7 Hz, 2H), 2.53 (s, 2H), 1.74 (m, J = 11.3, 4.9 Hz, 1H), 1.57 (d, J = 13.0 Hz, 2H), 1.13 (m, J = 13.6, 6.7 Hz, 2H). 70 6-methyl-4-(piperidine-1- ¹H NMR (400 MHz, DMSO-d₆) δ 12.14 (s, 260.2 carbonyl)-1H- 1H), 7.39 (s, 1H), 7.33 (d, J = 2.8 Hz, 1H), pyrrolo[2,3-c]pyridin-7- 6.24 (d, J = 2.7 Hz, 1H), 3.53 (s, 3H), 3.44 (t, one J = 5.3 Hz, 2H), 2.88 (d, J = 10.4 Hz, 2H), 1.76-1.55 (m, 2H), 1.55-1.37 (m, 4H). 71 6-methyl-4-(4- ¹H NMR (400 MHz, DMSO-d₆) δ 12.15 (s, 336.2 phenylpiperidine-1- 1H), 7.46 (s, 1H), 7.35 (d, J = 2.8 Hz, 1H), carbonyl)-1H- 7.33-7.24 (m, 4H), 7.24-7.16 (m, 1H), pyrrolo[2,3-c]pyridin-7- 6.32 (d, J = 2.7 Hz, 1H), 4.20 (s, 2H), 3.54 (s, 3H), one 3.01 (t, J = 12.6 Hz, 2H), 2.87-2.73 (m, 1H), 1.79 (d, J = 12.8 Hz, 2H), 1.68-1.47 (m, 2H). 72 4-[4- ¹H NMR (400 MHz, DMSO-d₆) δ 12.15 (s, 304.2 (methoxymethyl)piperidine- 1H), 7.39 (s, 1H), 7.33 (d, J = 2.7 Hz, 1H), 1-carbonyl]-6-methyl- 6.24 (d, J = 2.7 Hz, 1H), 4.05 (s, 2H), 3.53 (s, 1H-pyrrolo[2,3- 3H), 3.24 (d, J = 7.3 Hz, 4H), 3.19 (d, J = 6.3 Hz, c]pyridin-7-one 2H), 2.88-2.77 (m, 2H), 1.66 (d, J = 12.8 Hz, 2H), 1.21-1.00 (m, 2H). 73 6-methyl-4-(2-oxa-7- ¹H NMR (400 MHz, DMSO-d₆) δ 12.15 (s, 302.1 azaspiro[3.5]nonane-7- 1H), 7.40 (s, 1H), 7.33 (d, J = 2.8 Hz, 1H), carbonyl)-1H- 6.25 (d, J = 2.8 Hz, 1H), 4.33 (s, 4H), 3.52 (s, pyrrolo[2,3-c]pyridin-7- 3H), 3.40 (t, J = 5.7 Hz, 4H), 1.83-1.72 (m, one 4H). 74 N,N-dimethyl-1-(6- ¹H NMR (400 MHz, DMSO-d₆) δ 12.15 (s, 331.2 methyl-7-oxo-1H- 1H), 7.43 (s, 1H), 7.34 (t, J = 2.2 Hz, 1H), pyrrolo[2,3-c]pyridine-4- 6.23 (d, J = 2.7 Hz, 1H), 4.07 (s, 2H), 3.53 (s, carbonyl)piperidine-4- 3H), 3.08-2.71 (m, 7H), 2.64 (d, J = 8.0 Hz, carboxamide 2H), 1.64 (t, J = 8.0 Hz, 2H), 1.57-1.35 (m, 2H), 1.10 (s, 0H). 75 4-[4- ¹H NMR (400 MHz, DMSO-d₆) δ 12.14 (s, 290.2 (hydroxymethyl)piperidine- 1H), 7.40 (s, 1H), 7.33 (d, J = 2.8 Hz, 1H), 1-carbonyl]-6-methyl- 6.24 (d, J = 2.7 Hz, 1H), 4.49 (d, J = 5.7 Hz, 1H-pyrrolo[2,3- 1H), 4.06 (s, 2H), 3.53 (s, 3H), 3.28-3.17 (m, c]pyridin-7-one 2H), 2.92-2.81 (m, 2H), 1.76-1.53 (m, 3H), 1.17-0.96 (m, 2H). 76 6-methyl-4-[4-[2-(4- ¹H NMR (400 MHz, DMSO-d₆) δ 12.15 (s, 365.2 pyridyl)ethyl]piperidine- 1H), 8.49-8.39 (m, 2H), 7.40 (s, 1H), 1-carbonyl]-1H- 7.33 (d, J = 2.8 Hz, 1H), 7.24 (d, J = 5.6 Hz, 1H), pyrrolo[2,3-c]pyridin-7- 6.25 (d, J = 2.9 Hz, 1H), 4.05 (s, 2H), 3.53 (s, one 3H), 2.96-2.74 (m, 2H), 2.68-2.54 (m, 2H), 7.22-7.17 (m, 0H), 1.73 (d, J = 12.5 Hz, 2H), 1.65-1.39 (m, 4H), 1.20-0.99 (m, 2H). 77 6-methyl-4-(4-pyrrolidin- ¹H NMR (400 MHz, DMSO-d₆) δ 12.14 (s, 329.2 1-ylpiperidine-1- 1H), 7.41 (s, 1H), 7.33 (d, J = 2.8 Hz, 1H), carbonyl)-1H- 6.24 (d, J = 2.8 Hz, 1H), 3.93 (s, 2H), 3.53 (s, pyrrolo[2,3-c]pyridin-7- 3H), 3.08-2.96 (m, 2H), 2.48-2.44 (m, 4H), one 2.26-2.15 (m, 1H), 1.86-1.78 (m, 2H), 1.72-1.62 (m, 4H), 1.43-1.28 (m, 2H). 78 4-[4-(dimethylamino)-3- ¹H NMR (400 MHz, DMSO-d6) δ 7.38 (s, 317.2 methyl-piperidine-1- 1H), 7.32 (d, J = 2.7 Hz, 1H), 6.21 (d, J = 2.7 Hz, carbonyl]-6-methyl-1H- 1H), 3.53 (s, 3H), 2.86 (d, J = 17.9 Hz, pyrrolo[2,3-c]pyridin-7- 2H), 2.15 (m, 2H), 2.12 (s, 6H), 1.95 (dt, J = 11.5, one 4.0 Hz, 1H), 1.69 (d, J = 12.7 Hz, 1H), 1.33 (dt, J = 12.5, 6.3 Hz, 1H), 0.80 (dd, J = 22.1, 6.9 Hz, 4H). 79 4-[4- ¹H NMR (400 MHz, DMSO-d6) δ 12.19 (s, 331.2 (diethylamino)piperidine- 1H), 7.44 (s, 1H), 7.35 (t, J = 2.8 Hz, 1H), 1-carbonyl]-6-methyl- 6.29 (t, J = 2.4 Hz, 1H), 4.16 (m, 2H), 3.54 (s, 1H-pyrrolo[2,3- 3H), 3.11-2.80 (m, 6H), 1.93 (s, 2H), 1.55 (s, c]pyridin-7-one 2H), 1.18 (t, J = 7.1 Hz, 6H). 80 6-methyl-N-(m-tolyl)-7- 1H NMR (400 MHz, DMSO-d6) d 282 oxo-1H-pyrrolo[2,3- 12.07-12.21 (m, 1H), 9.84 (s, 1H), 8.03 (s, 1H), c]pyridine-4- 7.57 (s, 1H), 7.48-7.53 (m, 1H), 7.35 (t, J = 2.70 Hz, carboxamide 1H), 7.22 (s, 1H), 6.86-6.92 (m, 1H), 6.72 (t, J = 2.39 Hz, 1H), 3.60 (s, 3H), 2.31 (s, 3H). 81 N-cyclopropyl-6-methyl- ¹H NMR (400 MHz, DMSO-d₆) δ 12.05 (s, 328 N-(1-methyl-4- 1H), 7.93 (d, J = 4.2 Hz, 1H), 7.76 (s, 1H), piperidyl)-7-oxo-1H- 7.33-7.27 (m, 1H), 6.72-6.66 (m, 1H), pyrrolo[2,3-c]pyridine-4- 3.53 (s, 3H), 3.06 (d, J = 8.7 Hz, 2H), 2.95 (d, J = 3.8 Hz, carboxamide 1H), 2.42-2.32 (m, 3H), 1.57 (s, 2H), 0.98 (d, J = 6.2 Hz, 6H). 82 N-cyclopropyl-6-methyl- ¹H NMR (400 MHz, DMSO-d₆) δ 12.03 (s, 356 7-oxo-N-(1-propyl-4- 1H), 7.45 (s, 1H), 7.28 (d, J = 2.8 Hz, 1H), piperidyl)-1H- 6.25 (d, J = 2.7 Hz, 1H), 3.89 (tt, J = 12.1, 3.9 Hz, pyrrolo[2,3-c]pyridine-4- 1H), 3.53 (s, 3H), 3.30 (d, J = 16.5 Hz, carboxamide 2H), 2.96-2.89 (m, 2H), 2.72-2.61 (m, 1H), 2.26-2.17 (m, 2H), 2.10-1.95 (m, 2H), 1.94-1.83 (m, 2H), 1.82-1.74 (m, 2H), 1.50-1.36 (m, 2H), 0.85 (t, J = 7.4 Hz, 3H), 0.61-0.51 (m, 2H), 0.47-0.38 (m, 2H).

Example 83 N-(cyclopentylmethyl)-6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carboxamide

To a 1 dram vial was added cyclopentylmethanamine hydrochloride (34 mg, 0.25 mmol) followed by 6-methyl-7-oxo-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridine-4-carboxylic acid (Intermediate E) (Step 1, 0.5 mL, 0.25 mmol, 0.5 M in DMF), HATU (0.76 mL, 0.38 mmol, 0.5 M in DMF) and triethylamine (3 equiv., 0.75 mmol). The reaction was shaken at room temperature overnight. The DMF was removed under reduced pressure, and then methanol (1.5 mL) and potassium hydroxide (1 mL, 1.0 mmol, IM in water) were added. The reaction was heated at 60° C. overnight. After cooling the reaction was partitioned between dichloromethane and water. The organic solution was separated and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (5-85% ACN/0.1% NH4OH in H2O) yielding N-(cyclopentylmethyl)-6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carboxamide. (7.5 mg, 11%). ¹H NMR (400 MHz, DMSO-d₆) δ 12.05 (s, 1H), 7.93 (t, J=5.8 Hz, 1H), 7.79 (s, 1H), 7.31 (t, J=2.4 Hz, 1H), 6.72-6.66 (m, 1H), 3.55 (s, 3H), 3.23-3.07 (m, 2H), 2.14 (p, J=7.4 Hz, 1H), 1.76-1.65 (m, 2H), 1.65-1.44 (m, 4H), 1.33-1.19 (m, 2H). LCMS M/Z (M+H) 274.

The following compounds were prepared in a similar manner to Example 83:

Examples 84-138

Example Compound Name NMR m/z 84 N-(2-methoxyethyl)-6- ¹H NMR (400 MHz, DMSO-d₆) δ 12.14 (s, 346 methyl-N-(1-methyl-4- 1H), 7.37-7.24 (m, 2H), 6.17 (dd, J = 2.7, 1.9 Hz, piperidyl)-7-oxo-1H 1H), 3.71 (d, J = 12.1 Hz, 1H), 3.52 (s, pyrrolo[2,3-c]pyridine-4- 3H), 3.49-3.36 (m, 2H), 3.23 (s, 2H), carboxamide 2.95-2.77 (m, 2H), 2.18 (s, 2H), 1.98-1.80 (m, 4H), 1.71-1.56 (m, 2H). 85 6-methyl-4-(2- ¹H NMR (400 MHz, DMSO-d6) δ 12.07 (br. 322 phenylpyrrolidine-1- s., 1H), 7.48-7.85 (m, 1H), 7.09-7.44 (m, carbonyl)-1H- 6H), 6.34 (br. s., 1H), 5.27-6.10 (m, 3H), pyrrolo[2,3-c]pyridin-7- 5.14 (br. s., 1H), 3.82 (br. s., 1H), 3.38-3.73 (m, one 2H), 2.37 (dd, J = 6.23, 12.46 Hz, 1H), 1.66-1.97 (m, 2H). 86 N-(cyclohexylmethyl)-6- ¹H NMR (400 MHz, DMSO-d6) d 11.96 (bs, 288 methyl-7-oxo-1H- 1H), 7.81 (t, J = 5.49 Hz, 1H), 7.71 (s, 1H), pyrrolo[2,3-c]pyridine-4- 7.19-7.23 (m, 1H), 6.59 (d, J = 2.44 Hz, 1H), carboxamide 3.50-4.00 (bs, 3H), 2.98 (t, J = 6.35 Hz, 2H), 1.34-1.72 (m, 6H), 0.98-1.15 (m, 3H), 0.70-0.90 (m, 2H). 87 N-benzyl-N,6-dimethyl- ¹H NMR (400 MHz, DMSO-d6) d 12.05 (br. 296 7-oxo-1H-pyrrolo[2,3- s., 1H), 7.39 (s, 1H), 7.05-7.33 (m, 6H), c]pyridine-4- 6.14 (bs, 1H), 4.54 (s, 2H), 3.27-3.50 (m, 3H), carboxamide 2.65-2.86 (m, 3H). 88 6-methyl-4-(1,2,3,5- ¹H NMR (400 MHz, DMSO-d6) δ 12.14 (br. 323 tetrahydro-1,4- s., 1H), 7.28-7.34 (m, 1H), 7.14-7.27 (m, benzodiazepine-4- 1H), 7.06 (t, J = 7.48 Hz, 1H), 6.85 (d, J = 7.89 Hz, carbonyl)-1H- 1H), 6.74 (br. s., 1H), 6.20-6.24 (m, 1H), pyrrolo[2,3-c]pyridin-7- 4.56 (br. s., 2H), 3.70 (br. s., 1H), 3.45 (s, 3H), one 3.15 (br. s., 2H). 89 6-methyl-4-(3- ¹H NMR (400 MHz, DMSO-d6) d = 12.09 (br. 322 phenylpyrrolidine-1- s., 1 H), 7.55 (s, 1 H), 7.39-7.26 (m, 5 H), carbonyl)-1H- 7.26-7.18 (m, 1 H), 6.38 (t, J = 2.4 Hz, 1 H), pyrrolo[2,3-c]pyridin-7- 3.88 (br. s, 1 H), 3.73-3.31 (m, 7 H), 2.26 (br. one s., 1 H), 2.07 (s, 1 H). 90 N-[(1S)-2-amino-2-oxo- ¹H NMR (400 MHz, DMSO-d6) δ 325 1-phenyl-ethyl]-6- 12.00-12.38 (m, 1H), 8.16-8.25 (m, 1H), 8.04 (s, methyl-7-oxo-1H- 1H), 7.72-7.81 (m, 1H), 7.47-7.56 (m, 2H), pyrrolo[2,3-c]pyridine-4- 7.36 (s, 5H), 6.67-6.72 (m, 1H), carboxamide 5.56-5.63 (m, 1H), 3.56 (s, 3H). 91 N-benzhydryl-6-methyl- ¹H NMR (400 MHz, DMSO-d6) δ 358 7-oxo-1H-pyrrolo[2,3- 11.95-12.18 (m, 1H), 8.69-8.87 (m, 1H), 8.05 (s, c]pyridine-4- 1H), 7.32-7.41 (m, 7H), 7.30 (s, 3H), carboxamide 6.64-6.73 (m, 1H), 6.33-6.41 (m, 1H), 3.56 (s, 3H). 92 6-methyl-N-[(4- ¹H NMR (400 MHz, DMSO-d6) d = 12.12 (br. 360 methylsulfonylphenyl)methyl]- s., 1 H), 8.65 (t, J = 5.9 Hz, 1 H), 7.94 (s, 1 H), 7-oxo-1H- 7.92-7.85 (m, 2 H), 7.60 (d, J = 8.5 Hz, 2 H), pyrrolo[2,3-c]pyridine-4- 7.33 (t, J = 2.8 Hz, 1 H), 6.80-6.69 (m, 1 H), carboxamide 4.56 (d, J = 5.8 Hz, 2 H), 3.56 (s, 3 H), 3.19 (s, 3H). 93 methyl (2S)-2- ¹H NMR (400 MHz, DMSO-d6) δ 12.09 (br. 346 cyclohexyl-2-[(6-methyl- s., 1H), 8.08 (d, J = 7.69 Hz, 1H), 7.97 (s, 1H), 7-oxo-1H-pyrrolo[2,3- 7.32 (t, J = 2.80 Hz, 1H), 6.68 (t, J = 2.39 Hz, c]pyridine-4- 1H), 4.33 (t, J = 7.69 Hz, 1H), 3.65 (s, 3H), carbonyl)amino]acetate 3.57 (s, 3H), 1.56-1.88 (m, 4H), 1.00-1.30 (m, 6H). 94 N-[(1R)-1- . ¹H NMR (400 MHz, DMSO-d6) δ 12.05 (br. 302 cyclohexylethyl]-6- s., 1H), 7.81 (s, 1H), 7.63 (d, J = 8.52 Hz, 1H), methyl-7-oxo-1H- 7.30 (t, J = 2.70 Hz, 1H), 6.68 (t, J = 2.39 Hz, pyrrolo[2,3-c]pyridine-4- 1H), 3.77-3.91 (m, 1H), 3.53-3.58 (m, 3H), carboxamide 1.66-1.81 (m, 4H), 1.61 (d, J = 9.14 Hz, 1H), 1.39 (dd, J = 3.43, 7.17 Hz, 1H), 1.12-1.26 (m, 2H), 1.09 (d, J = 6.65 Hz, 3H), 0.89-1.04 (m, 2H). 95 N-[(1S)-2-methoxy-1- ¹H NMR (400 MHz, DMSO-d6) δ 12.09 (br. 326 phenyl-ethyl]-6-methyl- s., 1H), 8.33 (d, J = 8.10 Hz, 1H), 7.94 (s, 1H), 7-oxo-1H-pyrrolo[2,3- 7.39-7.46 (m, 2H), 7.29-7.38 (m, 3H), c]pyridine-4- 7.21-7.28 (m, 1H), 6.68 (t, J = 2.39 Hz, 1H), carboxamide 5.21-5.30 (m, 1H), 3.64-3.71 (m, 1H), 3.58 (s, 3H), 3.53-3.57 (m, 2H), 3.30 (s, 3H). 96 (2S)-2-[(6-methyl-7-oxo- ¹H NMR (400 MHz, DMSO-d6) δ 12.94 (br. 326 1H-pyrrolo[2,3- s., 1H), 12.10 (br. s., 1H), 8.48 (d, J = 7.27 Hz, c]pyridine-4- 1H), 8.04 (s, 1H), 7.50 (d, J = 7.27 Hz, 2H), carbonyl)amino]-2- 7.31-7.43 (m, 3H), 6.73 (s, 1H), 5.56 (d, J = 7.06 Hz, phenyl-acetic acid 1H), 3.34 (br. s., 3H). 97 N-[(1R)-2-amino-2-oxo- ¹H NMR (400 MHz, DMSO-d6) δ 12.15 (br. 325 1-phenyl-ethyl]-6- s., 1H), 8.21 (d, J = 7.48 Hz, 1H), 8.04 (s, 1H), methyl-7-oxo-1H- 7.76 (s, 1H), 7.51 (d, J = 7.27 Hz, 2H), pyrrolo[2,3-c]pyridine-4- 7.34-7.39 (m, 3H), 7.26-7.32 (m, 2H), 6.70 (t, J = 2.39 Hz, carboxamide 1H), 5.60 (d, J = 7.69 Hz, 1H), 3.56 (s, 3H). 98 N-[(1S)-1-carbamoyl-2- ¹H NMR (400 MHz, DMSO-d6) δ 12.14 (br. 291 methyl-propyl]-6-methyl- s., 1H), 7.96 (s, 1H), 7.57 (d, J = 8.72 Hz, 1H), 7-oxo-1H-pyrrolo[2,3- 7.52 (s, 1H), 7.35 (t, J = 2.80 Hz, 1H), 7.13 (s, c]pyridine-4- 1H), 6.68 (t, J = 2.29 Hz, 1H), 4.35 (dd, J = 6.65, carboxamide 8.72 Hz, 1H), 3.55-3.60 (m, 3H), 2.03-2.14 (m, 1H), 0.93 (t, J = 6.54 Hz, 6H). 99 1-(6-methyl-7-oxo-1H- ¹H NMR (400 MHz, DMSO-d6) δ 12.06 (br. 289 pyrrolo[2,3-c]pyridine-4- s., 1H), 7.57 (br. s., 1H), 7.24-7.40 (m, 2H), carbonyl)pyrrolidine-2- 6.94 (br. s., 1H), 6.39 (br. s., 1H), 4.41 (br. s., carboxamide 1H), 3.60 (br. s., 2H), 2.11-2.25 (m, 1H), 1.68-1.94 (m, 3H). 100 6-methyl-7-oxo-N- ¹H NMR (400 MHz, DMSO-d6) δ 12.06 (br. 290 (tetrahydropyran-3- s., 1H), 7.96 (t, J = 5.82 Hz, 1H), 7.81 (s, 1H), ylmethyl)-1H- 7.31 (t, J = 2.80 Hz, 1H), 6.58-6.74 (m, 1H), pyrrolo[2,3-c]pyridine-4- 3.76-3.84 (m, 1H),3.71 (td, J = 3.61, 11.06 Hz, carboxamide 1H), 3.54 (s, 3H), 3.31 (dt, J = 2.80, 10.75 Hz, 1H), 3.00-3.19 (m, 3H), 1.71-1.87 (m, 2H), 1.53-1.64 (m, 1H), 1.45 (m, 1H), 1.13-1.32 (m, 1H). 101 6-methyl-7-oxo-N- ¹H NMR (400 MHz, DMSO-d6) d 12.06 (bs, 290 (tetrahydropyran-4- 1H), 7.98 (t, J = 5.77 Hz, 1H), 7.82 (s, 1H), ylmethyl)-1H- 7.30 (t, J = 2.61 Hz, 1H), 6.68 (t, J = 2.47 Hz, pyrrolo[2,3-c]pyridine-4- 1H), 3.60-3.97 (m, 5H), 3.26 (dt, J = 1.79, carboxamide 11.60 Hz, 2H), 3.13 (t, J = 6.32 Hz, 2H), 1.76 (dt, J = 4.12, 7.55 Hz, 1H), 1.60 (d, J = 12.91 Hz, 2H), 1.05-1.32 (m, 3H). 102 6-methyl-7-oxo-N- ¹H NMR (400 MHz, DMSO-d6) d 12.07 (br. 276 (tetrahydrofuran-3- s., 1H), 8.06 (t, J = 5.91 Hz, 1H), 7.80 (s, 1H), ylmethyl)-1H- 7.31 (t, J = 2.75 Hz, 1H), 6.68 (t, J = 2.47 Hz, pyrrolo[2,3-c]pyridine-4- 1H), 3.57-3.80 (m, 2H), 3.54 (s, 2H), carboxamide 3.47 (dd, J = 5.22, 8.51 Hz, 1H), 3.10-3.27 (m, 1H), 1.94 (dd, J = 5.63, 12.22 Hz, 1H), 1.45-1.70 (m, 1H). 103 N-(cycloheptylmethyl)-6- ¹H NMR (400 MHz, DMSO-d6) d 12.06 (bs, 302 methyl-7-oxo-1H- 1H), 7.93 (t, J = 5.77 Hz, 1H), 7.81 (s, 1H), pyrrolo[2,3-c]pyridine-4- 7.31 (t, J = 2.75 Hz, 1H), 6.68 (t, J = 2.33 Hz, carboxamide 1H), 3.07 (t, J = 6.04 Hz, 2H), 1.26-1.75 (m, 11H), 1.04-1.25 (m, 2H). 104 6-methyl-7-oxo-N- ¹H NMR (400 MHz, DMSO-d6) d 12.05 (bs, 262 tetrahydrofuran-3-yl-1H- 1H), 8.09 (d, J = 6.32 Hz, 1H), 7.86 (s, 1H), pyrrolo[2,3-c]pyridine-4- 7.30 (t, J = 2.61 Hz, 1H), 6.69 (s, 1H), 4.43 (d, carboxamide J = 5.77 Hz, 1H), 3.78-3.92 (m, 2H), 3.65-3.78 (m, 2H), 2.14 (dd, J = 7.14, 12.63 Hz, 1H), 1.71-1.97 (m, 1H). 105 N-[(1,1-dioxothiolan-3- ¹H NMR (400 MHz, DMSO-d6) δ 12.10 (br. 324 yl)methyl]-6-methyl-7- s., 1H), 8.16 (t, J = 5.71 Hz, 1H), 7.84 (s, 1H), oxo-1H-pyrrolo[2,3- 7.33 (t, J = 2.80 Hz, 1H), 6.70 (t, J = 2.18 Hz, c]pyridine-4- 1H), 3.54-3.58 (m, 3H), 3.30-3.44 (m, 2H), carboxamide 3.16-3.30 (m, 2H), 3.02-3.13 (m, 1H), 2.87 (dd, J = 9.56, 13.09 Hz, 1H), 2.60-2.73 (m, 1H), 2.24 (d, J = 4.78 Hz, 1H), 1.79-1.92 (m, 1H). 106 6-methyl-N-(1- ¹H NMR (400 MHz, DMSO-d6) δ 12.05 (br. 314 norbornan-2-ylethyl)-7- s., 1H), 7.75-7.82 (m, 1H), 7.57-7.74 (m, oxo-1H-pyrrolo[2,3- 1H), 7.23-7.36 (m, H), 6.59-6.75 (m, 1H), c]pyridine-4- 3.60-3.92 (m, 2H), 3.52-3.58 (m, 3H), carboxamide 2.10-2.30 (m, 2H), 1.91 (br. s., 1H), 1.72 t, J = 11.84 Hz, 1H), 0.99-1.61 (m, 11H), 0.65-0.85 (m, 1H). 107 N-[(1R,2S)-2-hydroxy- ¹H NMR (400 MHz, DMSO-d6) δ 388 1,2-diphenyl-ethyl]-6- 11.99-12.13 (m, 1H), 8.09-8.21 (m, 1H), 7.63 (s, methyl-7-oxo-1H- 1H), 7.33-7.42 (m, 4H), 7.15-7.32 (m, 7H), pyrrolo[2,3-c]pyridine-4- 6.44 (s, 1H), 5.49-5.57 (m, 1H), carboxamide 5.11-5.21 (m, 1H), 4.87-4.97 (m, 1H), 3.53 (s, 3H). 108 N-(chroman-3-ylmethyl)- ¹H NMR (400 MHz, DMSO-d₆) δ 12.06 (s, 338 6-methyl-7-oxo-1H- 1H), 8.13 (t, J = 5.8 Hz, 1H), 7.86 (s, 1H), pyrrolo[2,3-c]pyridine-4- 7.32 (t, J = 2.7 Hz, 1H), 7.11-7.03 (m, 2H), carboxamide 6.86-6.79 (m, 1H), 6.78-6.69 (m, 2H), 4.28-4.20 (m, 1H), 3.92-3.84 (m, 1H), 3.56 (s, 2H), 3.30 (s, 3H), 2.91-2.81 (m, 1H), 2.71-2.53 (m, 1H), 2.28 (s, 1H). 109 tert-butyl 3-[(6-methyl-7- ¹H NMR (400 MHz, DMSO-d₆) δ 12.05 (s, 361 oxo-1H-pyrrolo[2,3- 1H), 8.08 (d, J = 6.6 Hz, 1H), 7.85 (s, 1H), c]pyridine-4- 7.31 (t, J = 2.5 Hz, 1H), 6.74-6.62 (m, 1H), carbonyl)amino]pyrrolidine- 4.39 (s, 1H), 3.55 (s, 4H), 3.51-3.35 (m, 1H), 1-carboxylate 3.28-3.26 (m, 1H), 3.18 (s, 1H), 2.10 (s, 1H), 1.98-1.73 (m, 1H), 1.41 (s, 9H). 110 N-(2,3- ¹H NMR (400 MHz, DMSO-d₆) δ 12.06 (s, 324 dihydrobenzofuran-2- 1H), 8.17 (t, J = 5.8 Hz, 1H), 7.77 (s, 1H), ylmethyl)-6-methyl-7- 7.31 (t, J = 2.6 Hz, 1H), 7.23-7.16 (m, 1H), oxo-1H-pyrrolo[2,3- 7.14-7.04 (m, 1H), 6.86-6.72 (m, 2H), c]pyridine-4- 6.72-6.63 (m, 1H), 5.01-4.91 (m, 1H), 3.53 (s, 5H), carboxamide 3.29-3.26 (m, 1H), 3.08-2.95 (m, 1H). 111 N-(2,3-dihydro-1,4- ¹H NMR (400 MHz, DMSO-d₆) δ 12.08 (s, 340 benzodioxin-3-ylmethyl)- 1H), 8.23 (t, J = 5.8 Hz, 1H), 7.89 (s, 1H), 6-methyl-7-oxo-1H- 7.34-7.26 (m, 1H), 6.92-6.80 (m, 4H), 6.73 (d, J = 2.7 Hz, pyrrolo[2,3-c]pyridine-4- 1H), 4.41-4.29 (m, 2H), carboxamide 4.05-3.97 (m, 1H), 3.65-3.45 (m, 5H). 112 N-(1-cyclopropylethyl)- ¹H NMR (400 MHz, DMSO-d₆) δ 12.03 (s, 260 6-methyl-7-oxo-1H- 1H), 7.80 (d, J = 9.9 Hz, 2H), 7.30 (d, J = 2.7 Hz, pyrrolo[2,3-c]pyridine-4- 1H), 6.69 (d, J = 2.7 Hz, 1H), 3.56 (s, 3H), carboxamide 3.53-3.43 (m, 1H), 1.21 (d, J = 6.7 Hz, 3H), 1.05-0.85 (m, 1H), 0.51-0.26 (m, 3H), 0.26-0.14 (m, 1H). 113 6-methyl-N-[3- ¹H NMR (400 MHz, DMSO-d₆) δ 9.90 (s, 1H), 367 (morpholinomethyl)phenyl]- 8.31 (s, 2H), 8.06 (s, 1H), 7.73-7.62 (m, 2H), 7-oxo-1H- 7.34 (d, J = 2.7 Hz, 1H), 7.31-7.24 (m, 1H), pyrrolo[2,3-c]pyridine-4- 7.04-6.98 (m, 1H), 6.73 (d, J = 2.7 Hz, 1H), carboxamide 3.60 (s, 3H), 3.58 (s, 3H), 3.45 (s, 2H), 2.43-2.30 (m, 4H). 114 6-methyl-N-(1- ¹H NMR (400 MHz, DMSO-d₆) δ 12.07 (s, 332 naphthylmethyl)-7-oxo- 1H), 8.50 (s, 1H), 8.26-8.14 (m, 1H), 1H-pyrrolo[2,3- 8.02-7.82 (m, 3H), 7.61-7.45 (m, 4H), 7.32 (t, J = 2.7 Hz, c]pyridine-4- 1H), 6.77-6.72 (m, 1H), 4.94 (d, J = 5.6 Hz, carboxamide 2H), 3.53 (s, 3H). 115 6-methyl-7-oxo-N-[1-(4- ¹H NMR (400 MHz, DMSO-d₆) δ 12.06 (s, 297 pyridyl)ethyl]-1H- 1H), 8.54-8.48 (m, 2H), 8.43 (d, J = 7.5 Hz, pyrrolo[2,3-c]pyridine-4- 1H), 7.97 (s, 1H), 7.41-7.37 (m, 2H), 7.30 (d, carboxamide J = 2.7 Hz, 1H), 6.67 (d, J = 2.7 Hz, 1H), 5.10 (t, J = 7.2 Hz, 1H), 3.58 (s, 3H), 1.47 (d, J = 7.1 Hz, 3H). 116 N-[1-(2- ¹H NMR (400 MHz, DMSO-d₆) δ 12.04 (s, 314 fluorophenyl)ethyl]-6- 1H), 8.38 (d, J = 7.6 Hz, 1H), 7.97 (s, 1H), methyl-7-oxo-1H- 7.56-7.45 (m, 1H), 7.33-7.24 (m, 2H), pyrrolo[2,3-c]pyridine-4- 7.22-7.10 (m, 2H), 6.68-6.64 (m, 1H), 537 (p, J = 7.1 Hz, carboxamide 1H), 3.58 (s, 3H), 1.46 (d, J = 7.0 Hz, 3H). 117 N-(2-ethoxypropyl)-6- ¹H NMR (400 MHz, DMSO-d₆) δ 12.07 (s, 278 methyl-7-oxo-1H- 1H), 7.84 (d, J = 9.9 Hz, 2H), 7.33 (d, J = 2.7 Hz, pyrrolo[2,3-c]pyridine-4- 1H), 6.69 (d, J = 2.7 Hz, 1H), carboxamide 3.63-3.40 (m, 6H), 3.28-3.21 (m, 2H), 1.11 (t, J = 6.8 Hz, 6H). 118 N-[1-(2- ¹H NMR (400 MHz, DMSO-d₆) δ 12.04 (s, 331 chlorophenyl)ethyl]-6- 1H), 8.46 (d, J = 7.4 Hz, 1H), 8.00 (s, 1H), methyl-7-oxo-1H- 7.61-7.52 (m, 1H), 7.47-7.38 (m, 1H), pyrrolo[2,3-c]pyridine-4- 7.37-7.21 (m, 3H), 6.68-6.64 (m, 1H), 5.42 (t, J = 7.1 Hz, carboxamide 1H), 3.59 (s, 3H), 1.44 (d, J = 7.0 Hz, 3H). 119 N-[1-(2- ¹H NMR (400 MHz, DMSO-d₆) δ 12.04 (s, 326 methoxyphenyl)ethyl]-6- 1H), 8.21 (d, J = 8.0 Hz, 1H), 7.96 (s, 1H), methyl-7-oxo-1H- 7.40-7.33 (m, 1H), 7.30 (t, J = 2.4 Hz, 1H), pyrrolo[2,3-c]pyridine-4- 7.27-7.17 (m, 1H), 7.03-6.95 (m, 1H), carboxamide 6.95-6.87 (m, 1H), 6.66-6.63 (m, 1H), 5.47-5.35 (m, 1H), 3.85 (s, 3H), 3.58 (s, 3H), 1.38 (d, J = 7.0 Hz, 3H). 120 N-[1-(2,3-dihydro-1,4- ¹H NMR (400 MHz, DMSO-d₆) δ 12.03 (s, 354 benzodioxin-6-yl)ethyl]- 1H), 8.20 (d, J = 7.9 Hz, 1H), 7.90 (s, 1H), 6-methyl-7-oxo-1H- 7.29 (t, J = 2.2 Hz, 1H), 6.89 (d, J = 2.1 Hz, pyrrolo[2,3-c]pyridine-4- 1H), 6.86-6.82 (m, 1H), 6.78 (d, J = 8.3 Hz, carboxamide 1H), 6.69-6.66 (m, 1H), 5.03 (t, J = 7.3 Hz, 1H), 4.23-4.17 (m, 4H), 3.56 (s, 3H), 1.41 (d, J = 7.0 Hz, 3H). 121 N-isochroman-4-yl-6- ¹H NMR (400 MHz, DMSO-d₆) δ 12.05 (s, 324 methyl-7-oxo-1H- 1H), 8.28 (d, J = 8.4 Hz, 1H), 7.95 (s, 1H), pyrrolo[2,3-c]pyridine-4- 7.37-7.30 (m, 2H), 7.29-7.21 (m, 2H), carboxamide 7.15-7.09 (m, 1H), 6.77 (d, J = 2.7 Hz, 1H), 5.29-5.13 (m, 1H), 4.83-4.67 (m, 2H), 4.04-3.91 (m, 1H), 3.86-3.75 (m, 1H), 3.52 (s, 3H). 122 6-methyl-N-[1-methyl-2- ¹H NMR (400 MHz, DMSO-d₆) δ 12.05 (s, 315 (3-methylisoxazol-5- 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.77 (s, 1H), yl)ethyl]-7-oxo-1H- 7.31 (d, J = 2.8 Hz, 1H), 6.66 (d, J = 2.7 Hz, pyrrolo[2,3-c]pyridine-4- 1H), 6.14 (s, 1H), 4.37-4.23 (m, 1H), 3.55 (s, carboxamide 3H), 3.07-2.85 (m, 2H), 2.17 (s, 3H), 1.19 (d, J = 6.6 Hz, 3H). 123 6-methyl-N-(2-methyl-1- ¹H NMR (400 MHz, DMSO-d₆) δ 12.03 (s, 324 phenyl-propyl)-7-oxo- 1H), 8.21 (d, J = 8.8 Hz, 1H), 7.87 (s, 1H), 1H-pyrrolo[2,3- 7.45-7.12 (m, 6H), 6.62 (m, J = 2.9, 1.3 Hz, c]pyridine-4- 1H), 4.70 (t, J = 8.9 Hz, 1H), 3.57 (s, 3H), carboxamide 2.10 (m, J = 9.1, 6.6 Hz, 1H), 1.02 (d, J = 6.6 Hz, 3H), 0.74 (d, J = 6.7 Hz, 3H). 124 N-[4-(4- ¹H NMR (400 MHz, DMSO-d₆) δ 11.98 (s, 356 fluorophenyl)tetrahydrofuran- 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.41 (s, 1H), 3-yl]-6-methyl-7- 7.32-7.26 (m, 2H), 7.22 (t, J = 2.4 Hz, 1H), oxo-1H-pyrrolo[2,3- 7.07 (t, J = 8.9 Hz, 2H), 6.33-6.30 (m, 1H), c]pyridine-4- 4.92-4.81 (m, 1H), 4.18-4.10 (m, 2H), carboxamide 4.07-3.99 (m, 1H), 3.82-3.74 (m, 1H), 3.73-3.64 (m, 1H), 3.47 (s, 3H). 125 6-methyl-7-oxo-N- ¹H NMR (400 MHz, DMSO-d₆) δ 12.04 (s, 322 tetralin-1-yl-1H- 1H), 8.24 (d, J = 8.6 Hz, 1H), 7.91 (s, 1H), pyrrolo[2,3-c]pyridine-4- 7.32 (t, J = 2.6 Hz, 1H), 7.27-7.21 (m, 1H), carboxamide 7.19-7.08 (m, 3H), 6.79-6.75 (m, 1H), 5.31-5.15 (m, 1H), 3.52 (s, 3H), 3.28-3.26 (m, 1H), 2.86-2.69 (m, 2H), 2.05-1.91 (m, 2H), 1.87-1.71 (m, 1H). 126 N-[1-(4- ¹H NMR (400 MHz, DMSO-d₆) δ 12.04 (s, 331 chlorophenyl)ethyl]-6- 1H), 8.34 (d, J = 7.7 Hz, 1H), 7.93 (s, 1H), methyl-7-oxo-1H- 7.48-7.33 (m, 3H), 7.29 (t, J = 2.7 Hz, 1H), pyrrolo[2,3-c]pyridine-4- 6.67 (d, J = 2.0 Hz, 1H), 5.12 (t, J = 7.2 Hz, carboxamide 1H), 3.57 (s, 3H), 1.46 (d, J = 7.1 Hz, 3H). 127 6-methyl-N-[2-(o- ¹H NMR (400 MHz, DMSO-d₆) δ 310 tolyl)ethyl]-7-oxo-1H- 12.32-12.04 (m, 1H), 7.48 (s, 1H), 7.32 (d, J = 2.8 Hz, pyrrolo[2,3-c]pyridine-4- 1H), 7.26-7.05 (m, 4H), 6.24 (d, J = 2.8 Hz, carboxamide 1H), 4.70 (s, 2H), 3.74 (t, J = 5.9 Hz, 2H), 3.54 (s, 3H), 3.27 (d, J = 0.9 Hz, 1H), 2.94-2.73 (m, 3H). 128 N,6-dimethyl-7-oxo-N- ¹H NMR (400 MHz, DMSO-d₆) δ 12.13 (s, 310 (1-phenylethyl)-1H- 1H), 7.64-7.07 (m, 8H), 5.62 (d, J = 16.2 Hz, pyrrolo[2,3-c]pyridine-4- 1H), 3.53 (s, 3H), 3.27 (s, 1H), 2.63 (s, 3H), carboxamide 1.57 (d, J = 7.0 Hz, 3H). 129 N-[1-(4- ¹H NMR (400 MHz, DMSO-d₆) δ 12.04 (s, 314 fluorophenyl)ethyl]-6- 1H), 8.31 (d, J = 7.8 Hz, 1H), 7.92 (s, 1H), methyl-7-oxo-1H- 7.46-7.39 (m, 2H), 7.29 (t, J = 2.5 Hz, 1H), pyrrolo[2,3-c]pyridine-4- 7.18-7.10 (m, 2H), 6.69-6.65 (m, 1H), carboxamide 5.14 (t, J = 7.3 Hz, 1H), 3.57 (s, 3H), 1.46 (d, J = 7.1 Hz, 3H). 130 tert-butyl 3-[[(6-methyl- ¹H NMR (400 MHz, DMSO-d₆) δ 12.07 (s, 361 7-oxo-1H-pyrrolo[2,3- 1H), 8.10 (t, J = 5.8 Hz, 1H), 7.32 (t, J = 2.5 Hz, c]pyridine-4- 1H), 6.73-6.63 (m, 1H), 3.87 (d, J = 8.8 Hz, carbonyl)amino]methyl]azetidine- 2H), 3.55 (s, 5H), 3.47-3.39 (m, 2H), 1-carboxylate 3.27 (t, J = 0.8 Hz, 1H), 2.82-2.63 (m, 1H), 1.36 (s, 9H). 131 6-methyl-N-(1-methyl-1- ¹H NMR (400 MHz, DMSO-d₆) δ 12.02 (s, 310 phenyl-ethyl)-7-oxo-1H- 1H), 7.95 (d, J = 15.2 Hz, 2H), 7.45-7.35 (m, pyrrolo[2,3-c]pyridine-4- 2H), 7.33-7.24 (m, 3H), 7.21-7.12 (m, 1H), carboxamide 6.63-6.55 (m, 1H), 3.58 (s, 3H), 1.67 (s, 6H). 132 tert-butyl 2-[[6-methyl- ¹H NMR (400 MHz, DMSO-d₆) δ 12.04 (s, 390 7-oxo-1H-pyrrolo[2,3- 1H), 7.90 (s, 1H), 7.78 (s, 1H), 7.31 (t, J = 2.5 Hz, c]pyridine-4- 1H), 6.76-6.66 (m, 1H), 4.35 (d, J = 7.0 Hz, carbonyl)amino]methyl]piperidine- 1H), 3.86 (d, J = 13.3 Hz, 1H), 3.54 (s, 1-carboxylate 3H), 3.36 (m, J = 13.1, 6.3 Hz, 1H), 3.27 (s, 1H), 2.93 (s, 1H), 1.71-1.34 (m, 5H), 1.28 (s, 10H). 133 tert-butyl 4-[[(6-methyl- ¹H NMR (400 MHz, DMSO-d₆) δ 12.05 (s, 390 7-oxo-1H-pyrrolo[2,3- 1H), 7.97 (t, J = 5.8 Hz, 1H), 7.81 (s, 1H), c]pyridine-4- 7.31 (t, J = 2.7 Hz, 1H), 6.78-6.62 (m, 1H), carbonyl)amino]methyl]piperidine- 4.08-3.81 (m, 2H), 3.55 (s, 3H), 3.14 (t, J = 6.1 Hz, 1-carboxylate 2H), 2.85-2.60 (m, 2H), 1.84-1.57 (m, 3H), 1.39 (s, 9H), 1.18-0.89 (m, 2H). 134 tert-butyl 2-[[(6-methyl- ¹ H NMR (400 MHz, DMSO-d₆) δ 12.08 (s, 391 7-oxo-1H-pyrrolo[2,3- 1H), 8.03 (t, J = 5.8 Hz, 1H), 7.85 (s, 1H), c]pyridine-4- 7.32 (d, J = 2.8 Hz, 1H), 6.71 (d, J = 2.7 Hz, 1H), carbonyl)amino]methyl] 3.92-3.77 (m, 2H), 3.70 (d, J = 13.4 Hz, 1H), morpholine-4- 3.52-3.43 (m, 1H), 3.43-3.35 (m, 1H), carboxylate 3.33 (d, J = 6.0 Hz, 5H), 2.89 (s, 1H), 2.71-2.55 (m, 1H), 1.39 (s, 9H). 135 tert-butyl 3-[[(6-methyl- ¹H NMR (400 MHz, DMSO-d₆) δ 12.06 (s, 390 7-oxo-1H-pyrrolo[2,3- 1H), 7.98 (t, J = 5.8 Hz, 1H), 7.81 (s, 1H), c]pyridine-4- 7.32 (t, J = 2.7 Hz, 1H), 6.71 (d, J = 2.7 Hz, 1H), carbonyl)amino]methyl]piperidine- 3.89 (s, 1H), 3.76 (d, J = 13.2 Hz, 1H), 3.55 (s, 1-carboxylate 3H), 3.27 (s, 2H), 3.17-3.08 (m, 2H), 2.84-2.72 (m, 1H), 1.77 (d, J = 12.5 Hz, 1H), 1.71-1.56 (m, 2H), 1.36 (s, 10H), 1.22-1.12 (m, 1H). 136 tert-butyl 2-[[(6-methyl- ¹H NMR (400 MHz, DMSO-d₆) δ 12.05 (s, 275 7-oxo-1H-pyrrolo[2,3- 1H), 7.98 (s, 1H), 7.82 (s, 1H), 7.31 (t, J = 2.4 Hz, c]pyridine-4- 1H), 6.71 (s, 1H), 3.90 (s, 1H), 3.55 (s, carbonyl)amino]methyl]pyrrolidine- 3H), 1.41 (s, 9H). 1-carboxylate 137 tert-butyl 3-[[(6-methyl- ¹H NMR (400 MHz, DMSO-d₆) δ 12.06 (s, 375 7-oxo-1H-pyrrolo[2,3- 1H), 8.06 (t, J = 5.8 Hz, 1H), 7.82 (s, 1H), c]pyridine-4- 7.32 (t, J = 2.4 Hz, 1H), 6.72-6.66 (m, 1H), carbonyl)amino]methyl]pyrrolidine- 3.55 (s, 3H), 3.28-3.16 (m, 4H), 3.05-2.92 (m, 1-carboxylate 1H), 2.42 (s, 1H), 1.91 (d, J = 5.5 Hz, 1H), 1.58 (d, J = 28.8 Hz, 1H), 1.39 (s, 10H). 138 tert-butyl 3-[(6-methyl-7- ¹H NMR (400 MHz, DMSO-d₆) δ 12.06 (s, 375 oxo-1H-pyrrolo[2,3- 1H), 7.82 (s, 1H), 7.75 (d, J = 7.5 Hz, 1H), c]pyridine-4- 7.31 (t, J = 2.3 Hz, 1H), 6.70-6.65 (m, 1H), carbonyl)amino]piperidine- 4.05-3.59 (m, 3H), 3.55 (s, 3H), 3.27 (t, J = 0.7 Hz, 1-carboxylate 2H), 2.85 (t, J = 11.6 Hz, 1H), 1.90 (d, J = 8.4 Hz, 1H), 1.71 (s, 1H), 1.39 (s, 10H).

Example 139 N,6-dimethyl-7-oxo-N-(1-pyrimidin-4-yl-4-piperidyl)-1H-pyrrolo[2,3-c]pyridine-4-carboxamide

Step 1:

tert-butyl methyl(1-(pyrimidin-4-yl)piperidin-4-yl)carbamate

A mixture of tert-butyl methyl(piperidin-4-yl)carbamate (500 mg, 2.3 mmol), cesium carbonate (836 mg, 2.6 mmol) and 4-chloropyrimidine (294 mg, 2.6 mmol) in DMF (10 mL) was heated at 80° C. for 3 h, at which time LCMS indicated full conversion of starting material. The reaction mixture was poured into ice water (10 mL) and extracted with ethyl acetate (3×20 mL). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure to give the title compound (450 mg, 66.0% yield) as a yellow solid. This crude material was used in the next step without further purification.

Step 2:

N-methyl-1-(pyrimidin-4-yl)piperidin-4-amine hydrochloride

To a cooled (0° C.) solution of tert-butyl methyl(1-(pyrimidin-4-yl)piperidin-4-yl)carbamate (300 mg, 1.0 mmol) in ethyl acetate (50 mL) was added hydrogen chloride (2N in ethyl acetate, 10 mL). After addition, the reaction mixture was stirred at 25° C. for 3 h. The solvent was evaporated under reduced pressure to give the crude title compound (165 mg, 72% yield) as a yellow solid.

Step 3:

N,6-dimethyl-7-oxo-N-(1-pyrimidin-4-yl-4-piperidyl)-1H-pyrrolo[2,3-c]pyridine-4-carboxamide

A mixture of 6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-carboxylic acid (Intermediate C) (100 mg, 0.5 mmol), diisopropylethylamine (134 mg, 1.0 mmol), HATU (150 mg, 0.6 mmol) and 1-(pyrimidin-4-yl)piperidin-4-amine hydrochloride (110 mg, 0.5 mmol) in DMF (5 mL) was stirred at 25° C. for 3 h, at which time LCMS indicated the reaction had gone to completion. The reaction mixture was added to ice water (5 mL) and extracted with ethyl acetate (3×10 mL). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC, acetonitrile: water (10 nM ammonia): 32%-62%, to give the title compound (11 mg, 5.8% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d6): δ 12.12 (s, 1 H), 8.43 (d, J=9.6 Hz, 1 H), 8.12 (m, 1 H), 7.38 (s, 1 H), 7.30 (s, 1 H), 6.83 (d, J=6.4 Hz, 1 H), 6.19 (d, J=2.4 Hz, 1 H), 4.51-4.43 (m, 2 H), 4.43-4.25 (m, 1 H), 3.50 (s, 3 H), 2.91-2.81 (m, 2 H), 2.75 (s, 3 H), 1.76-1.63 (m, 4 H). LCMS M/Z (M+H) 367.2.

The following compounds were prepared in a similar fashion to Example 139.

Examples 140-158

Example Compound Name NMR m/z 140 N,6-dimethyl-N-[1-(5- ¹H NMR (400 MHz, DMSO-d6): δ 381 methylpyrimidin-2-yl)-4- 12.15 (br. s., 1 H), 8.21 (s, 2 H), 7.41 (s, 1 H), piperidyl]-7-oxo-1H- 7.33 (s, 1 H), 6.22 (s, 1 H), 4.72 (d, J = 12.4 Hz, pyrrolo[2,3-c]pyridine-4- 2 H), 4.39-4.31 (m, 1 H), 3.53 (s, carboxamide 3 H), 2.79-2.74 (m, 5 H), 2.07 (s, 3 H), 1.69-1.66 (m, 4 H) 141 N-[1-(5-cyanopyrimidin-2- ¹H NMR (400 MHz, DMSO-d6): δ 392 yl)-4-piperidyl]-N,6- 12.15 (br. s., 1 H), 8.75-8.72 (m, 2 H), 7.41 (s, 1 dimethyl-7-oxo-1H- H), 7.33 (s, 1 H), 6.22 (d, J = 3.2 Hz, 1 pyrrolo[2,3-c]pyridine-4- H), 4.85-4.81 (m, 2 H), 4.48-4.42 (m, 1 carboxamide H), 3.53 (s, 3 H), 3.05-2.96 (m, 2 H), 2.79 (s, 3 H), 1.78-1.72 (m, 4 H) 142 N,6-dimethyl-7-oxo-N-[1- ¹H NMR (400 MHz, DMSO-d6): δ 435 [4- 12.15 (br. s., 1 H), 8.67 (d, J = 4.4 Hz, 1 H), (trifluoromethyl)pyrimidin- 7.42 (s, 1 H), 7.33 (s, 1 H), 7.00 (d, J = 5.2 Hz, 2-yl]-4-piperidyl]-1H- 1 H), 6.22 (s, 1 H), 4.79-4.75 (m, pyrrolo[2,3-c]pyridine-4- 2 H), 4.47-4.39 (m, 1 H), 3.53 (s, 3 H), carboxamide 2.99-2.92 (m., 2 H), 2.80 (s, 3 H), 1.77-1.70 (m, 4 H) 143 N,6-dimethyl-7-oxo-N-(1- ¹H NMR (400 MHz, DMSO-d6): δ 367 pyrazin-2-yl-4-piperidyl)- 12.13 (br. s., 1 H), 8.34 (s, 1 H), 8.06 (s, 1 H), 1H-pyrrolo[2,3-c]pyridine- 7.80 (d, J = 2.4 Hz, 1 H), 7.41 (s, 1 H), 4-carboxamide 7.38-7.31 (m, 1 H), 6.22 (s, 1 H), 4.47-4.34 (m, 3 H), 3.53 (s, 3 H), 2.86-2.79 (m, 5 H), 1.78-1.71 (m, 4 H) 144 N,6-dimethyl-N-[1-(4- ¹H NMR (400 MHz, CD₃OD): δ 8.14 (d, J = 5.2 Hz, 381 methylpyrimidin-2-yl)-4- 1 H), 7.40-7.39 (m, 2 H), piperidyl]-7-oxo-1H- 6.47 (d, J = 5.2 H z, 1 H), 6.36 (d, J = 2.8 Hz, 1 pyrrolo[2,3-c]pyridine-4- H), 4.88 (s, 3 H), 3.67 (s, 3 H), carboxamide 2.93-2.75 (m, 5 H), 2.32 (s, 3 H), 1.87-1.81 (m, 4 H). 145 N,6-dimethyl-7-oxo-N-(1- ¹H NMR (400 MHz, DMSO-d6): δ 367 pyridazin-3-yl-4- 12.15 (br. s., 1 H), 8.52 (d, J = 3.6 Hz, 1 H), piperidyl)-1H-pyrrolo[2,3- 7.42-7.26 (m, 4 H), 6.23 (d, J = 2.4 Hz, 1 c]pyridine-4-carboxamide H), 4.50 (d, J = 12.4 Hz, 2 H), 4.38-4.32 (m, 1 H), 3.54 (s, 3 H), 2.91-2.85 (m, 2 H), 2.80 (s, 3 H), 1.83-1.75 (m, 4 H). 146 N-[1-(4-cyanopyrimidin-2- ¹H NMR (400 MHz, DMSO-d6): δ 392 yl)-4-piperidyl]-N,6- 12.10 (br. s., 1 H), 8.62 (d, J = 4.5 Hz, 1 H), dimethyl-7-oxo-1H- 7.40 (s, 1 H), 7.33 (s, 1 H), 7.11 (d, J = 4.5 Hz, pyrrolo[2,3-c]pyridine-4- 1 H), 6.22 (s, 1 H), 4.74-4.72 (m, carboxamide 2 H), 4.38-4.30 (m, 1 H), 3.53 (s, 3 H), 2.96-2.86 (m, 2 H), 2.79-2.76 (m, 3 H), 1.76-1.70 (m, 4 H) 147 N-[1-(5-fluoropyrimidin-2- ¹H NMR (400 MHz, DMSO-d6): δ 385 yl)-4-piperidyl]-N,6- 12.15 (s, 1 H), 8.44 (s, 2 H), 7.41 (s, 1 H), dimethyl-7-oxo-1H- 7.33 (s, 1 H), 6.22 (s, 1 H), 4.70-4.65 (m, 2 H), pyrrolo[2,3-c]pyridine-4- 3.53 (s, 3 H), 3.31-3.28 (m, 1 H), carboxamide 2.90-2.86 (m, 2 H), 2.79 (s, 3 H), 2.67 (s, 1 H), 1.72-1.70 (m, 4 H). 148 6-methyl-7-oxo-N-(1- ¹H NMR (400 MHz, DMSO-d6): δ 353 pyrimidin-4-yl-4- 12.05 (s, 1 H), 8.48 (s, 1 H), 8.16 (d, J = 6.4 Hz, piperidyl)-1H-pyrrolo[2,3- 1 H), 7.85-7.79 (m, 2 H), 7.30 (d, J = 2.4 Hz, c]pyridine-4-carboxamide 1 H), 6.87 (d, J = 6.4 Hz, 1 H), 6.68 (d, J = 2.8 Hz, 1 H), 4.38-4.34 (m, 2 H), 4.10-4.08 (m, 1 H), 3.53 (s, 3 H), 3.25-3.04 (m, 2 H), 1.90-1.87 (m, 2 H), 1.46-1.43 (m, 2 H). 149 6-methyl-N-[1-(5- ¹H NMR (400 MHz, DMSO-d6): δ 367 methylpyrimidin-2-yl)-4- 12.03 (s, 1 H), 8.20 (s, 1 H), 7.80-7.78 (m, 2 H), piperidyl]-7-oxo-1H- 7.28 (d, J = 2.4 Hz, 1 H), 6.67 (d, J = 2.8 Hz, pyrrolo[2,3-c]pyridine-4- 1 H), 4.56-4.53 (m, 2 H), carboxamide 4.10-3.90 (m, 1 H), 3.51 (s, 3 H), 3.03-2.96 (m, 2 H), 2.06 (s, 3 H), 1.85-1.83 (m, 2 H), 1.44-1.39 (m, 2 H). 150 6-methyl-N-[1-(4- ¹H NMR (400 MHz, DMSO-d6): δ 367 methylpyrimidin-2-yl)-4- 12.03 (s, 1 H), 8.19 (d, J = 5.2 Hz, 1 H), piperidyl]-7-oxo-1H- 7.81-7.78 (m, 2 H), 7.28 (s, 1 H), 6.67 (s, 1 H), pyrrolo[2,3-c]pyridine-4- 6.47 (d, J = 5.2 Hz, 1 H), 4.63-4.59 (m, 2 carboxamide H), 4.05-4.02 (m, 1 H), 3.51 (s, 3 H), 2.99 (t, J = 11.6 Hz, 2 H), 2.25 (s, 3 H), 1.86-1.84 (m, 2 H), 1.47-1.42 (m, 2 H). 151 6-methyl-7-oxo-N-(1- ¹H NMR (400 MHz, DMSO-d6): δ 353 pyrazin-2-yl-4-piperidyl)- 12.07 (s, 1 H), 8.37 (d, J = 1.2 Hz, 1 H), 8.09 (d, 1H-pyrrolo[2,3-c]pyridine- J = 0.8 Hz, 1 H), 7.89-7.79 (m, 3 H), 4-carboxamide 7.31 (s, 1 H), 6.71 (s, 1 H), 4.36-4.32 (m, 2 H), 4.10-4.08 (m, 1 H), 3.54 (s, 3 H). 3.06 (t, J = 11.6 Hz, 2 H), 1.91-1.89 (m, 2 H), 1.56-1.47 (m, 2 H). 152 N-[1-(5-cyanopyrimidin-2- ¹H NMR (400 MHz, DMSO-d6): δ 378 yl)-4-piperidyl]-6-methyl- 12.06 (s, 1 H), 8.74 (s, 2 H), 7.87 (d, J = 7.2 Hz, 7-oxo-1H-pyrrolo[2,3- 1 H), 7.79 (s, 1 H), 7.29-7.28 (m, 1 H), c]pyridine-4-carboxamide 6.66 (s, 1 H), 4.65-4.61 (m, 2 H), 4.11-4.09 (m, 1 H), 3.52 (s, 3 H), 3.24-3.18 (m, 2 H), 1.94-1.91 (m, 2 H), 1.47-1.42 (m, 2 H). 153 6-methyl-7-oxo-N-[1-[4- ¹H NMR (400 MHz, DMSO-d6): δ 421 (trifluoromethyl)pyrimidin- 12.04 (s, 1 H), 8.66-8.63 (m, 1 H), 7.84-7.78 (m, 2-yl]-4-piperidyl]-1H- 2 H), 7.28 (d, J = 2.8 Hz, 1 H), pyrrolo[2,3-c]pyridine-4- 6.98-6.94 (m, 1 H), 6.66 (d, J = 2.8 Hz, 1 H), carboxamide 4.58-4.55 (m, 2 H), 4.08-4.06 (m, 1 H), 3.50 (s, 3 H), 3.15-3.12 (m, 2 H), 1.91-1.86 (m, 2 H), 1.49-1.41 (m, 2 H). 154 N-[1-(5-fluoropyrimidin-2- ¹H NMR (400 MHz, DMSO-d6): δ 371 yl)-4-piperidyl]-6-methyl- 12.05 (s, 1 H), 8.43 (s, 2 H), 7.84-7.79 (m, 2 H), 7-oxo-1H-pyrrolo[2,3- 7.29-7.28 (m, 1 H), 6.67 (s, 1 H), c]pyridine-4-carboxamide 4.52-4.48 (m, 2 H), 4.06-4.03 (m, 1 H), 3.51 (s, 3 H), 3.05 (t, J = 11.6 Hz, 2 H), 1.87-1.84 (m, 2 H), 1.48-1.40 (m, 2 H). 155 6-methyl-7-oxo-N-(1- ¹H NMR (400 MHz, DMSO-d6): δ 353 pyridazin-3-yl-4- 12.07 (s, 1 H), 8.53 (d, J = 3.6 Hz, 1 H), piperidyl)-1H-pyrrolo[2,3- 7.87-7.82 (m, 2 H), 7.39-7.29 (m, 3 H), 6.71 (s, c]pyridine-4-carboxamide 1 H), 4.40-4.36 (m, 2 H), 4.11-4.10 (m, 1 H), 3.54 (s, 3 H), 3.08 (t, J = 11.6 Hz, 2 H), 1.92-1.89 (m, 2 H), 1.58-1.50 (m, 2 H). 156 N-[1-(4-cyanopyrimidin-2- ¹H NMR (400 MHz, DMSO-d6): δ 378 yl)-4-piperidyl]-6-methyl- 12.08 (s, 1 H), 8.66 (d, J = 4.5 Hz, 1 H), 7-oxo-1H-pyrrolo[2,3- 7.88-7.82 (m, 2 H), 7.32 (s, 1 H), 7.15 (d, J = 4.5 Hz, c]pyridine-4-carboxamide 1 H), 6.70 (s, 1 H), 4.57-4.54 (m, 2 H), 4.12-4.10 (m, 1 H), 3.55 (s, 3 H), 3.16 (t, J = 11.6 Hz, 2 H), 1.95-1.92 (m, 2 H), 1.53-1.45 (m, 2H). 157 N,6-dimethyl-7-oxo-N-[(1- ¹H NMR (400 MHz, DMSO-d₆) δ 381 pyrimidin-2-yl-4- 12.14-12.09 (m, 2H), 8.31 (d, J = 4.7 Hz, 2H), piperidyl)methyl]-1H- 7.41 (s, 1H), 7.35-7.29 (m, 1H), 6.56 (t, pyrrolo[2,3-c]pyridine-4- J = 4.7 Hz, 1H), 6.23-6.16 (m, 1H), carboxamide 4.62 (d, J = 12.8 Hz, 2H), 3.53 (s, 3H), 3.38-3.33 (m, 2H), 2.98 (s, 3H), 2.92-2.81 (m, 2H), 2.05-2.00 (m, 1H), 1.68-1.63 (m, 2H), 1.04-0.99 (m, 2H). 158 N,6-dimethyl-7-oxo-N-[(1- 1H NMR (400 MHz, DMSO-d6) δ 381 pyrimidin-4-yl-4- 12.08 (s, 1H), 8.44 (s, 1H), 8.12 (d, J = 6.2 Hz, piperidyl)methyl]-1H- 1H), 7.39 (s, 1H), 7.32 (d, J = 2.8 Hz, 1H), pyrrolo[2,3-c]pyridine-4- 6.78 (d, J = 6.3 Hz, 1H), 6.26-6.11 (m, carboxamide 1H), 4.36 (d, J = 13.0 Hz, 2H), 3.52 (s, 3H), 3.41-3.32 (m, 2H), 2.97 (s, 3H), 2.95-2.83 (m, 2H), 2.22-1.95 (m, 1H), 1.79-1.51 (m, 2H), 1.21-0.96 (m, 2H).

Example 159 6-allyl-N-methyl-7-oxo-N-[1-[4-(tri oromethyl)pyrimidin-2-yl]-4-piperidyl]-1H-pyrrolo[2,3-c]pyridine-4-carboxamide

Step 1:

6-allyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carboxylic acid

Sodium hydride, 60% in mineral oil (870 mg, 21.65 mmol) was added in 3 portions to a cooled (0° C.) solution of methyl 7-oxo-1-(p-tolylsulfonyl)-6H-pyrrolo[2,3-c]pyridine-4-carboxylate (Intermediate B, 5.0 g, 14.43 mmol) in DMF (70 mL). The reaction was stirred for 30 min at room temperature and 3-bromoprop-1-ene (1.37 mL, 15.88 mmol) was added. The reaction was warmed (50° C.) and stirring was continued for 3h. The reaction was quenched with minimal methanol, and then water (100 mL) was added. The mixture was extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-5% methanol: dichloromethane) yielding 1.96 of ester intermediate as a white solid that was immediately carried forward.

Potassium hydroxide (1.42 g, 25.4 mmol) in water (10 mL) was added to a solution of methyl 6-allyl-7-oxo-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridine-4-carboxylate (1.96 g, 1.0 equiv., 5.07 mmol) in methanol (25 mL). The reaction was stirred at 45° C. for 1 h. The reaction was then cooled to room temperature, and the methanol was evaporated under reduced pressure. The aqueous solution was acidified to pH 2 using 3N hydrochloric acid, and the resulting precipitate was collected by filtration. The filter cake was washed with water and dried, yielding title compound (1.18 g, 37%). LCMS M/Z (M+H) 219.

Step 2:

6-allyl-N-methyl-7-oxo-N-[[4-(trifluoromethyl)pyrimidin-2-yl]-4-piperidyl]-1H-pyrrolo[2,3-c]pyridine-4-carboxamide

To an 8 mL vial was added 6-allyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carboxylic acid (Step 1.50 mg, 0.23 mmol), N,N-dimethylformamide (1 mL), HATU (1.05 equiv., 0.24 mmol), and triethylamine (4 equiv., 0.92 mmol). The reaction vial was capped and vortexed for one minute. N-methyl-1-(4-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-amine hydrochloride (62 mg, 0.27 mmol, as prepared in example 139) was added and the reaction vial shaken at room temperature overnight. The reaction mixture was diluted with dichloromethane and washed with water. The organic solution was then concentrated under reduced pressure and the residue was purified by HPLC (20-60% ACN/0.1% NH4OH in H2O) yielding title compound (32 mg, 36%). ¹H NMR (400 MHz, DMSO-d6) δ 12.14 (s, 1H), 8.47 (d, J=1.2 Hz, 1H), 8.15 (d, J=6.2 Hz, 1H), 7.43-7.25 (m, 2H), 6.85 (dd, J=6.4, 1.3 Hz, 1H), 6.24 (t, J=2.3 Hz, 1H), 5.99 (ddt, J=17.2, 10.5, 5.3 Hz, 1H), 5.17 (dq, J=10.3, 1.4 Hz, 1H), 5.13-5.01 (m, 1H), 4.72-4.58 (m, 2H), 4.51 (d, J=13.1 Hz, 2H), 4.33 (s, 1H), 2.79 (s, 5H), 1.72 (td, J=11.4, 10.2, 3.8 Hz, 4H). LCMS M/Z (M+H) 393.

The following compounds were prepared in a similar fashion to Example 159.

Examples 160-168

Example Compound Name NMR m/z 160 6-allyl-N-[1-(2- 1H NMR (400 MHz, DMSO-d6) δ 12.15 (s, 1H), 418 cyanopyrimidin-4- 8.67 (d, J = 4.8 Hz, 1H), 7.43-7.22 (m, 2H), yl)-4-piperidyl]-N- 6.99 (d, J = 4.8 Hz, 1H), 6.30-6.19 (m, 1H), methyl-7-oxo-1H- 6.12-5.89 (m, 1H), 5.25-5.13 (m, 1H), 5.13-5.01 (m, 1H), pyrrolo[2,3- 4.77 (d, J = 13.0 Hz, 2H), 4.64 (d, J = 5.4 Hz, 2H), c]pyridine-4- 4.36 (s, 1H), 2.93 (s, 2H), 2.80 (s, 3H), carboxamide 1.90-1.60 (m, 4H). 161 6-allyl-N-methyl-7- 1H NMR (400 MHz, DMSO-d6) δ 12.14 (s, 1H), 393 oxo-N-(1-pyrimidin- 8.47 (d, J = 1.2 Hz, 1H), 8.15 (d, J = 6.2 Hz, 1H), 4-yl-4-piperidyl)- 7.43-7.25 (m, 2H), 6.85 (dd, J = 6.4, 1.3 Hz, 1H), 1H-pyrrolo[2,3- 6.24 (t, J = 2.3 Hz, 1H), 5.99 (ddt, J = 17.2, 10.5, 5.3 Hz, c]pyridine-4- 1H), 5.17 (dq, J = 10.3, 1.4 Hz, 1H), carboxamide 5.13-5.01 (m, 1H), 4.72-4.58 (m, 2H), 4.51 (d, J = 13.1 Hz, 2H), 4.33 (s, 1H), 2.79 (s, 514), 1.72 (td, J = 11.4, 10.2, 3.8 Hz, 4H). 162 6-allyl-N-[1-(6- 1H NMR (400 MHz, DMSO-d6) δ 12.15 (s, 1H), 423 methoxypyrimidin- 8.23 (d, J = 0.8 Hz, 1H), 7.34 (d, J = 2.8 Hz, 1H), 4-yl)-4-piperidyl]-N- 7.30 (s, 1H), 6.24 (d, J = 2.7 Hz, 1H), 6.10 (d, J = 0.9 Hz, methyl-7-oxo-1H- 1H), 6.06-5.91 (m, 1H), 5.21-5.12 (m, pyrrolo[2,3- 1H), 5.12-5.01 (m, 1H), 4.64 (dt, J = 5.5, 1.5 Hz, c]pyridine-4- 2H), 4.45 (d, J = 13.1 Hz, 2H), 4.30 (s, 1H), 3.81 (s, carboxamide 3H), 3.37-3.25 (m, 1H), 2.78 (s, 5H), 1.74-1.62 (m, 4H). 163 6-allyl-N-[1-(6,7- 1H NMR (400 MHz, DMSO-d6) δ 12.16 (s, 1H), 433 dihydro-5H- 8.30 (s, 1H), 7.35 (d, J = 2.8 Hz, 1H), 7.29 (s, 1H), cyclopenta[d]pyrimidin- 6.23 (d, J = 2.8 Hz, 1H), 6.06-5.91 (m, 1H), 4-yl)-4- 5.17 (dq, J = 10.2, 1.4 Hz, 1H), 5.12-5.01 (m, 1H), piperidyl]-N-methyl- 4.67-4.60 (m, 2H), 4.51 (d, J = 13.1 Hz, 2H), 3.30 (s, 7-oxo-1H- 2H), 2.99 (t, J = 7.3 Hz, 2H), 2.94-2.85 (m, 2H), pyrrolo[2,3- 2.79 (s, 3H), 2.72 (dd, J = 15.7, 7.8 Hz, 2H), c]pyridine-4- 2.01-1.88 (m, 2H), 1.84-1.70 (m, 4H). carboxamide 164 6-allyl-N-methyl-7- 1H NMR (400 MHz, DMSO-d6) δ 12.16 (s, 1H), 461 oxo-N-[1-[6- 8.61 (d, J = 1.1 Hz, 1H), 7.38-7.27 (m, 3H), (trifluoromethyl)pyrimidin- 6.25 (d, J = 2.7 Hz, 1H), 6.06-5.92 (m, 1H), 4-yl]-4- 5.22-5.13 (m, 1H), 5.12-5.02 (m, 1H), 4.68-4.60 (m, 2H), piperidyl]-1H- 4.41-4.36 (m, 1H), 3.35-3.23 (m, 2H), 2.96 (s, pyrrolo[2,3- 2H), 2.79 (s, 3H), 1.79-1.72 (m, 4H). c]pyridine-4- carboxamide 165 6-allyl-N-[1-(2,6- 1H NMR (400 MHz, DMSO-d6) δ 12.16 (s, 1H), 421 dimethylpyrimidin- 7.38-7.27 (m, 2H), 6.53 (s, 1H), 6.28-6.21 (m, 4-yl)-4-piperidyl]-N- 1H), 6.06-5.91 (m, 1H), 5.21-5.13 (m, 1H), methyl-7-oxo-1H- 5.12-5.01 (m, 1H), 4.64 (dt, J = 5.4, 1.6 Hz, 2H), pyrrolo[2,3- 4.51 (d, J = 13.1 Hz, 2H), 4.31 (s, 1H), 2.81-2.76 (m, c]pyridine-4- 5H), 2.31 (s, 3H), 2.20 (s, 3H), 1.75-1.61 (m, 4H). carboxamide 166 6-allyl-N-methyl-7- 1H NMR (400 MHz, DMSO-d6) δ 12.15 (s, 1H), 435 oxo-N-[1-(6- 8.39 (d, J = 1.1 Hz, 1H), 7.38-7.28 (m, 2H), propylpyrimidin-4- 6.70 (d, J = 1.3 Hz, 1H), 6.24 (d, J = 2.8 Hz, 1H), yl)-4-piperidyl]-1H- 6.06-5.91 (m, 1H), 5.21-5.13 (m, 1H), 5.12-5.01 (m, pyrrolo[2,3- 1H), 4.67-4.60 (m, 2H), 4.52 (d, J = 12.9 Hz, 2H), c]pyridine-4- 3.35-3.25 (m, 16H), 2.85-2.76 (m, 5H), carboxamide 2.56-2.42 (m, 2H), 1.76-1.57 (m, 6H), 0.98-0.84 (m, 3H). 167 6-allyl-N-[1-(6- 1H NMR (400 MHz, DMSO-d6) δ 12.15 (s, 1H), 435 isopropylpyrimidin- 8.40 (d, J = 1.0 Hz, 1H), 7.38-7.28 (m, 2H), 4-yl)-4-piperidyl]-N- 6.68 (d, J = 1.2 Hz, 1H), 6.24 (d, J = 2.8 Hz, 1H), methyl-7-oxo-1H- 6.06-5.91 (m, 1H), 5.21-5.13 (m, 1H), 5.12-5.01 (m, pyrrolo[2,3- 1H), 4.67-4.50 (m, 4H), 3.30 (d, J = 19.9 Hz, 16H), c]pyridine-4- 2.86-2.71 (m, 5H), 1.77-1.66 (m, 4H), 1.17 (d, J = 6.9 Hz, carboxamide 6H). 168 6-allyl-N-[1-(2- 1H NMR (400 MHz, DMSO-d6) δ 12.15 (s, 1H), 447 cyclopropyl-6- 7.37-7.27 (m, 2H), 6.47 (s, 1H), 6.24 (d, J = 2.7 Hz, methyl-pyrimidin-4- 1H), 5.99 (ddt, J = 17.2, 10.5, 5.4 Hz, 1H), yl)-4-piperidyl]-N- 5.17 (dq, J = 10.3, 1.4 Hz, 1H), 5.06 (dq, J = 17.2, 1.6 Hz, methyl-7-oxo-1H- 1H), 4.64 (dt, J = 5.6, 1.6 Hz, 2H), 4.48 (d, J = 13.1 Hz, pyrrolo[2,3- 2H), 4.30 (s, 0H), 2.90-2.67 (m, 5H), 2.18 (s, c]pyridine-4- 3H), 1.89 (tt, J = 7.9, 4.9 Hz, 1H), 1.74-1.60 (m, carboxamide 4H), 0.93-0.79 (m, 4H).

Example 169 6-allyl-N-methyl-7-oxo-N-[1-(6-pyrazol-1-ylpyrazin-2-yl)-4-piperidyl]-1H-pyrrolo[2,3c]pyridine-4-carboxamide

Step 1:

2-chloro-6-(1H-pyrazol-1-yl)pyrazine

To a 40 mL vial was added 2,6-dichloropyrazine (4.0 g, 26.9 mmol), 1H-pyrazole (1.8 g, 26.9 mmol), potassium carbonate (7.4 g, 53.7 mmol), and 10 mL of N,N-dimethylacetamide. The reaction was capped and shaken at 50° C. for 2 hours, then cooled to room temperature and diluted with ethyl acetate. The organic was then washed with water, and concentrated under reduced pressure. The crude product was purified by flash column (10-35% Ethyl Acetate: Heptanes) yielding title compound as a white solid (1.51 g, 31%). ¹H NMR (400 MHz, DMSO-d₆) δ 9.24-9.12 (m, 2H), 8.80-8.68 (m, 2H), 8.68-8.54 (m, 2H), 7.96 (dd, J=1.7, 0.7 Hz, 2H), 6.74-6.63 (m, 2H), 3.38-3.24 (m, 1H). LCMS M/Z (M+H) 281.

Step 2:

6-allyl-N-methyl-7-oxo-N-(piperidin-4-yl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-carboxamide hydrochloride

To a round bottom flask was added 6-allyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carboxylic acid (2.3 g, 10.5 mmol Example 159, step 1) followed by N,N-dimethylformamide (20 mL), HATU (4.3 g, 11.1 mmol), triethylamine (5.9 mL, 42.2 mmol), and tert-butyl 4-(methylamino)-piperidine-1-carboxylate (2.9 g, 13.7 mmol). The reaction was stirred for 1 h, then was diluted with ethyl acetate, and washed with water. The organic was concentrated under reduced pressure. The crude product was purified by flash column (0-10% dichloromethane: methanol) yielding boc protected product.

The product was then taken up with 20 mL methanol, and 10 mL of 4N HCl in dioxane was added. The reaction was stirred at r.t. for 1 h, at which time mixture was concentrated under reduced pressure yielding product as HCl salt (2.0 g, 55% over two steps). The crude amine was carried on without further purification. LCMS M/Z (M+H) 315.

Step 3:

6-allyl-N-methyl-7-oxo-N-[1-(6-pyrazol-1-ylpyrazin-2-yl)-4-piperidyl]-1H-pyrrolo[2,3-c]pyridine-4-carboxamide

To a 4 mL vial was added 6-allyl-N-methyl-7-oxo-N-(4-piperidyl)-1H-pyrrolo[2,3-c]pyridine-4-carboxamide hydrochloride (40 mg, 0.11 mmol) followed by 2-chloro-6-pyrazol-1-yl-pyrazine (21 mg, 0.11 mmol), diisopropylethylamine (0.08 mL, 0.46 mmol), and 0.16 mL. The reaction was capped and shaken at 90° C. overnight. The reaction was cooled to room temperature, diluted with ethyl acetate, and washed with water. The organic was concentrated under reduced pressure, and the residue was purified by HPLC (20-60% ACN/0.1% NH4OH in H2O) yielding title compound (10 mg, 19%). 1H NMR (400 MHz, DMSO-d6) δ 12.15 (s, 1H), 8.59 (dd, J=2.6, 0.7 Hz, 1H), 8.38-8.17 (m, 2H), 7.82 (dd, J=1.7, 0.7 Hz, 1H), 7.42-7.21 (m, 2H), 6.57 (dd, J=2.6, 1.7 Hz, 1H), 6.25 (dd, J=2.8, 1.5 Hz, 1H), 6.07-5.89 (m, 1H), 5.24-5.13 (m, 1H), 5.13-5.02 (m, 1H), 4.67-4.61 (m, 2H), 4.57 (d, J=13.2 Hz, 2H), 4.35 (s, 1H), 3.04-2.86 (m, 2H), 2.81 (s, 3H), 1.95-1.68 (m, 4H). LCMS M/Z (M+H) 459.

Example 170 6-aryl-N-methyl-7-oxo-N-[1-(6-pyrazol-1-ylpyrimidin-4-yl)-4-piperidyl]-1H-pyrrolo[2,3-c]pyridine-4-carboxamide

Step 1

tert-butyl (1-(6-(1H-pyrazol-1-yl)pyrimidin-4-yl)piperidin-4-yl)(methyl)carbamate

To a solution of tert-butyl (1-(6-chloropyrimidin-4-yl)piperidin-4-yl)(methyl) carbamate (600 mg, 1.84 mmol) in DMF (10 mL) was added 1H-pyrazole (150 mg, 2.20 mmol) and cesium carbonate (1.2 g, 3.67 mmol). After addition, the reaction mixture was heated at 80° C. for 12 h, at which time LCMS indicated the reaction had gone to completion. After cooled, the solid was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (50 mL), washed with water (2×30 mL), dried over sodium sulfate and concentrated to give the crude title compound (500 mg, 76% yield) as a yellow solid.

Step 2

1-(6-(1H-pyrazol-1-yl)pyrimidin-4-yl)-N-methylpiperidin-4-amine hydrochloride

To a solution of tert-butyl (1-(6-(1H-pyrazol-1-yl)pyrimidin-4-yl)piperidin-4-yl)(methyl) carbamate (500 mg, 1.39 mmol) in ethyl acetate (10 mL) was added hydrogen chloride (2 N in ethyl acetate, 10 mL) at 0° C. After addition, the mixture was stirred at ambient temperature for 2 h, at which time LCMS indicated the reaction had gone to completion. The solution was concentrated under reduced pressure to give the crude title compound (400 mg, 97% yield) as a white solid.

Step 3

6-allyl-N-methyl-7-oxo-N-[1-(6-pyrazol-1-ylpyrimidin-4-yl)-4-piperidyl]-1H-pyrrolo[2,3-c]pyridine-4-carboxamide

To a solution of 1-(6-(1H-pyrazol-1-yl)pyrimidin-4-yl)-N-methylpiperidin-4-amine hydrochloride (216 mg, 0.73 mmol) in DMF (4 mL) was added 6-allyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-carboxylic acid (80 mg, 0.37 mmol), N-ethyl-N-isopropylpropan-2-amine (142 mg, 1.1 mmol) and HATU (181 mg, 0.48 mmol). After addition, the mixture was stirred at ambient temperature for 1.5 h, at which time LCMS indicated that the reaction had gone to completion. The solvent was removed under reduce pressure. The residue was dissolved in ethyl acetate (20 mL), washed with brine (2×15 mL) and concentrated. The crude product was purified by reverse phase chromatography (acetonitrile 40%/0.1% NH₄OH in water) to give the title compound (12.8 mg, 8% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 12.19 (s, 1 H), 8.68 (s, 1 H), 8.49 (s, 1 H), 7.91 (s, 1 H), 7.34 (d, J=11.6 Hz, 2 H), 7.24 (s, 1 H), 6.63 (s, 1 H), 6.24 (s, 1 H), 5.99-5.94 (m, 1 H), 5.16 (d, J=10.0 Hz, 1 H), 5.06 (d, J=17.2 Hz, 1 H), 4.64-4.40 (m, 5 H), 3.03 (s, 2 H), 2.78 (s, 3 H), 1.79 (s, 4 H). LCMS M/Z (M+H) 459.1.

Example 171 6-methyl-7-oxo-N-(1-phenyl-4-piperidyl)-1H-pyrrolo[2,3-c]pyridine-4-carboxamide

Step 1:

tert-butyl (1-phenylpiperidin-4-yl)carbamate

To a solution of tert-butyl piperidin-4-ylcarbamate (420 mg, 1.96 mmol) in dry xylene (8 mL) was added 1-iodo-4-methylbenzene (400 mg, 1.96 mmol), sodium tert-butoxide (564 mg, 5.88 mmol), Pd₂(dba)₃ (10 mg) and xantphos (15 mg). With nitrogen protection, the reaction mixture was heated at 120° C. under microwave conditions for 30 min, at which time LCMS indicated the reaction had gone to completion. The mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (Hexanes/ethyl acetate=5:1) to give the title compound (100 mg, 17.5% yield) that was used directly in step 2.

Step 2

1-phenylpiperidin-4-amine hydrochloride

To a solution of tert-butyl (1-phenylpiperidin-4-yl)carbamate (100 mg, 0.35 mmol) in ethyl acetate (10 mL) was added Hydrogen chloride (2 N in Ethyl acetate, 10 mL). The reaction mixture was stirred at ambient temperature for 30 min and then concentrated under reduced pressure to give the crude title compound as hydrogen chloride salt (60 mg, 78% yield). This material was used directly in the next step.

Step 3

6-methyl-7-oxo-N-(1-phenyl-4-piperidyl)-1H-pyrrolo[2,3-c]pyridine-4-carboxamide

To a solution of 1-phenylpiperidin-4-amine hydrochloride (60 mg, 0.28 mmol) in DMF (3 mL) was added 6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-carboxylic acid (Intermediate C) (65 mg, 0.34 mmol), HATU (128 mg, 0.34 mmol) and diisopropylethylamine (1 mL). The reaction mixture was stirred at ambient temperature for 4 h, at which time LCMS indicated that the reaction had gone to completion. The mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate (15 mL) and washed with water (2×10 mL). The organic solution was concentrated under reduced pressure and the residue was purified by preparative HPLC (basic-acetonitrile: water (10 nM ammonia)25%-55%) to give the title compound (20 mg, 15% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d6): δ 12.03 (s, 1 H), 7.85-7.79 (m, 2 H), 7.28 (s, 1 H), 7.19-7.15 (m, 2 H), 6.93-6.91 (m, 2 H), 6.72-6.65 (m, 2 H), 3.92-3.90 (m, 1 H), 3.71-3.68 (m, 2 H), 3.51 (s, 3 H), 2.78 (t, J=11.6 Hz, 2 H), 1.86-1.84 (m, 2 H), 1.63-1.55 (m, 2 H). LCMS M/Z (M+H) 351.1.

The following compounds were prepared in a similar fashion to Example 168.

Examples 172-180

Example Compound Name NMR m/z 172 N,6-dimethyl-7-oxo-N- ¹H NMR (400 MHz, DMSO-d6): δ 365 (1-phenyl-4-piperidyl)- 12.18-12.10 (br. s., 1 H), 7.41 (s, 1 H), 7.34 (s, 1 H), 1H-pyrrolo[2,3- 7.23-7.17 (m, 2 H), 6.93 (d, J = 8.0 Hz, 2 H), 6.75 (t, c]pyridine-4- J = 7.4 Hz, 1 H), 6.22 (s, 1 H), 4.28-4.15 (m, 1 carboxamide H), 3.77-3.71 (m, 2 H), 3.53 (s, 3 H), 2.83 (s, 3 H), 2.68-2.60 (m, 2 H), 1.93-1.85 (m, 2 H), 1.74-1.72 (m, 2 H) 173 N,6-dimethyl-N-[1-(m- ¹H NMR (400 MHz, CD₃OD): δ 7.43-7.41 (m, 2 379 tolyl)-4-piperidyl]-7- H), 7.12 (t, J = 7.6 Hz, 1 H), 6.84-6.80 (m, 2 H), oxo-1H-pyrrolo[2,3- 6.70 (d, J = 7.2 Hz, 1 H), 6.38 (d, J = 2.4 Hz, 1 c]pyridine-4- H), 3.80-3.60 (m, 5 H), 3.00 (s, 3 H), carboxamide 2.93-2.47 (m, 3 H), 2.30 (s, 3 H), 2.13-2.02 (m, 2 H), 1.94-1.82 (m, 2 H). 174 N,6-dimethyl-7-oxo-N- ¹ NMR (400 MHz, CD₃OD): δ 7.90-7.71 (m, 4 432 [1-[3- H), 7.43-7.39 (m, 2 H), 6.37 (d, J = 2.4 Hz, 1 H), (trifluoromethyl)phenyl]- 3.86-3.83 (m, 2 H), 3.66 (s, 4 H), 3.03 (s, 3 H), 4-piperidyl]-1H- 2.47-2.39 (m, 2 H), 2.16-2.13 (m, 2 H). pyrrolo[2,3-c]pyridine-4- carboxamide 175 N,6-dimethyl-7-oxo-N- ¹ H NMR (400 MHz, CD₃OD): δ 7.39-7.35 (m, 3 433 [1-[4- H), 7.18-7.14 (m, 2 H), 7.04 (d, J = 7.2 Hz, 1 H), (trifluoromethyl)phenyl]- 6.35 (d, J = 2.8 Hz, 1 H), 3.91-3.79 (m, 2 H), 4-piperidyl]-1H- 3.65 (s, 3 H), 3.36-3.34 (m, 1 H), 2.97 (s, 3 H), pyrrolo[2,3-c]pyridine-4- 2.84-2.74 (m, 2 H), 2.07-2.01 (m, 2 H), carboxamide 1.99-1.87 (m, 2 H). 176 N,6-dimethyl-7-oxo-N- ¹H NMR (400 MHz, CD₃OD): δ 7.47-7.36 (m, 2 379 [1-(p-tolyl)-4-piperidyl]- H), 7.06 (d, J = 8.0 Hz, 2 H), 6.91 (d, J = 7.2 Hz, 1H-pyrrolo[2,3- 2 H), 6.38 (d, J = 3.2 Hz, 1 H), 3.70-3.67 (m, 5 c]pyridine-4- H), 3.01 (s, 3 H), 2.87-2.53 (m, 3 H), 2.25 (s, 3 carboxamide H), 2.13-2.02 (m, 2 H), 1.89-1.83 (m, 2 H). 177 N-[1-(3-ethylphenyl)-4- ¹H NMR (400 MHz, CD₃OD): δ 7.43-7.42 (m, 2 393 piperidyl]-N,6-dimethyl- H), 7.18-7.12 (m, 1 H), 6.87-6.80 (m, 2 H), 7-oxo-1H-pyrrolo[2,3- 6.76-6.71 (m, 1 H), 6.38 (d, J = 2.8 Hz, 1 H), c]pyridine-4- 3.85-3.70 (m, 2 H), 3.68 (s, 3 H), 3.01 (s, 3 H), carboxamide 2.89-2.50 (m, 5 H), 2.13-2.03 (m, 2 H), 1.95-1.84 (m, 2 H), 1.22 (t, J = 8.0 Hz, 3 H). 178 N-[1-(4-ethylphenyl)-4- ¹H NMR (400 MHz, CD₃OD): δ 7.43-7.41 (m, 2 393 piperidyl]-N,6-dimethyl- H), 7.09 (d, J = 8.4 Hz, 2 H), 6.93 (d,J = 6.8 Hz, 7-oxo-1H-pyrrolo[2,3- 2 H), 6.38 (d, J = 2.4 Hz, 1 H), 3.75-3.60 (m, 5 c]pyridine-4- H), 3.01 (s, 3 H), 2.80-2.49 (m, 5 H), carboxamide 2.10-2.02 (m, 2 H), 1.90-1.79 (m, 2 H), 1.20 (t, J = 7.6 Hz, 3H). 179 N-[1-(3- ¹ H NMR (400 MHz, CD₃OD): δ 7.43-7.41 (m, 2 407 isopropylphenyl)-4- H), 7.16 (t, J = 7.8 Hz, 1 H), 6.87-6.72 (m, 3 H), piperidyl]-N,6-dimethyl- 6.38 (d, J = 3.2 Hz, 1 H), 3.83-3.71 (m, 2 H), 7-oxo-1H-pyrrolo[2,3- 3.68 (s, 3 H), 3.01 (s, 3 H), 2.97-2.46 (m, 4 H), c]pyridine-4- 2.13-2.03 (m, 2 H), 1.95-1.80 (m, 2 H), 1.24 (d, carboxamide J = 7.2 Hz, 6 H). 180 N-[1-(4- ¹H NMR (400 MHz, CD₃OD): δ 7.47-7.34 (m, 2 407 isopropylphenyl)-4- H), 7.12 (d, J = 8.4 Hz, 2 H), 6.94 (d, J = 7.2 Hz, piperidyl]-N,6-dimethyl- 2 H), 6.38 (d, J = 3.2 Hz, 1 H), 3.76-3.60 (m, 5 7-oxo-1H-pyrrolo[2,3- H), 3.01 (s, 3 H), 2.97-2.45 (m, 4 H), c]pyridine-4- 2.13-2.02 (m, 2 H), 1.90-1.82 (m, 2 H), 1.22 (d, J = 6.8 Hz, carboxamide 6 H).

Example 181 N,6-dimethyl-N-[2-(1-methyl-4-piperidyl)ethyl]-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carboxamide

Step 1:

tert-butyl 4-[2-[(6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carbonyl)amino]ethyl]piperidine-1-carboxylate

HATU (988 mg, 2.6 mmol) was added to a stirred mixture of 6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carboxylic acid (Intermediate C) (500 mg, 2.6 mmol), tert-butyl 4-(2-aminoethyl)piperidine-1-carboxylate (713 mg, 3.1 mmol), and diisopropylethylamine (1.0 g, 7.8 mmol) in DMF (10 mL). The reaction mixture was stirred at room temperature for 16 h, at which time LCMS indicated that the reaction had gone to completion. The reaction mixture was partitioned between ethyl acetate (50 mL) and water (15 mL). The separated organic solution was washed with brine (2×10 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography column (dichloromethane:methanol=10:1) to afford the title compound (800 mg, 72.4% yield) as a yellow solid. LCMS M/Z (M+H) 402.9.

Step 2:

tert-butyl 4-[2-[[6-methyl-7-oxo-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridine-4-carbonyl]amino]ethyl]piperidine-1-carboxylate

Sodium hydride (60%, 119 mg, 3.0 mmol) was added to a stirred and cooled (0° C.) solution of tert-butyl 4-[2-[(6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carbonyl)amino]ethyl]piperidine-1-carboxylate (800 mg, 2.0 mmol) in DMF (10 mL). Stirring was continued for 1 h at room temperature before 4-methylbenzene-1-sulfonyl chloride (455 mg, 2.4 mmol) was added. The reaction mixture was then stirred at room temperature for 1 h and quenched by addition of saturated aqueous ammonium chloride (2 mL). The reaction mixture was partitioned between ethyl acetate (150 mL) and water (50 mL). The organic layer was washed with brine (10 mL×2), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate=1:2) to afford the title compound (500 mg, 45.0% yield) as a white solid. LCMS M/Z (M+H) 556.8.

Step 3:

tert-butyl 4-[2-[methyl-[6-methyl-7-oxo-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridine-4-carbonyl]amino]ethyl]piperidine-1-carboxylate

Sodium hydride (60%, 54 mg, 1.4 mmol) was added to a stirred and cooled (0° C.) solution of tert-butyl 4-[2-[[6-methyl-7-oxo-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridine-4-carbonyl]amino]ethyl]piperidine-1-carboxylate (Step 2, 500 mg, 0.9 mmol) in DMF (10 mL). Stirring was continued for 1 h at room temperature before iodomethane (153 mg, 1.1 mmol) was added. The reaction mixture was then stirred at room temperature for 1 h and quenched by addition of saturated aqueous ammonium chloride (2 mL). The reaction mixture was partitioned between ethyl acetate (120 mL) and water (30 mL). The organic layer was washed with brine (10 mL×2), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate=1:1) to afford the title compound (350 mg, 68.3% yield) as a yellow solid. LCMS M/Z (M+H) 571.2.

Step 4:

N,6-dimethyl-7-oxo-N-[2-(4-piperidyl)ethyl]-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridine4 carboxamide hydrogen chloride

A mixture of tert-butyl 4-[2-[methyl-[6-methyl-7-oxo-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridine-4-carbonyl]amino]ethyl]piperidine-1-carboxylate (350 mg, 0.6 mmol) in 4 N Hydrogen chloride/ethyl acetate, (40 mmol, 10 mL) was stirred at room temperature for 2 h. The solvent was concentrated under reduced pressure to give the crude title compound as a yellow solid that was carried on to the next step. LCMS M/Z (M+H) 471.8.

Step 5:

N,6-dimethyl-N-[2-(1-methyl-4-piperidyl)ethyl]-7-oxo-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridine-4-carboxamide

A mixture of N,6-dimethyl-7-oxo-N-[2-(4-piperidyl)ethyl]-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridine-4-carboxamide hydrogen chloride (100 mg, 0.2 mol) and paraformaldehyde (7 mg, 0.2 mmol) in methanol (5 mL) was heated at 70° C. for 16 h. The solution was cooled to 0° C. and then sodium borohydride (12 mg, 0.3 mmol) was added. After addition, stirring was continued for 1 h at room temperature. The reaction mixture was quenched by addition of saturated aqueous ammonium chloride (5 mL). The resulting mixture was partitioned between ethyl acetate (30 mL) and water (10 mL). The separated organic solution was washed with brine (2×5 mL), dried over sodium sulfate and concentrated under reduced pressure to afford the crude title compound (100 mg, 97.1% yield) as a white solid. LCMS M/Z (M+H) 485.1.

Step 6:

N,6-dimethyl-N-[2-(1-methyl-4-piperidyl)ethyl]-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carboxamide

A mixture of N,6-dimethyl-N-[2-(1-methyl-4-piperidyl)ethyl]-7-oxo-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridine-4-carboxamide (100 mg, 0.2 mmol) in methanol (2 mL) and aqueous sodium hydroxide solution (20% wt/vol, 1 mL) was heated at 100° C. for 16 h. After cooling, the mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC, acetonitrile: water (10 nM ammonia), 10%-40%, to give the title compound (10 mg, 14.5% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d6): δ 12.11 (s, 1 H), 7.38-7.30 (m, 2H), 6.16 (d, J=3.2 Hz, 1 H), 3.50 (s, 3 H), 2.90 (s, 3 H), 2.65-2.64 (m, 2 H), 2.06 (s, 3 H), 1.73-1.49 (m, 7 H), 1.06-1.05 (m, 4 H). LCMS M/Z (M+H) 331.2.

The following compounds were prepared in a similar fashion to Example 181.

Examples 182-186

Example Compound Name NMR m/z 182 N-[2-(1-ethyl-4- ¹H NMR (400 MHz, CD₃OD): δ 8.52 (s, 1 H), 345 piperidyl)ethyl]-N,6- 7.41 (d, J = 3.6 Hz, 2 H), 6.37 (d, J = 2.4 Hz, 1 dimethyl-7-oxo-1H- H), 3.68-3.50 (m, 7 H), 3.13-3.32 (m, 5 H), pyrrolo[2,3-c]pyridine- 3.00-2.70 (m, 2 H), 2.14-2.10 (m, 1 H), 4-carboxamide 1.82-1.42 (m, 5 H), 1.34-1.21 (m, 4 H) 183 N-[2-(1-isopropyl-4- ¹H NMR (400 MHz, CD₃OD): δ 8.51 (s, 1 H), 359 piperidyl)ethyl]-N,6- 7.48-7.37 (m, 2 H), 6.38 (s, 1 H), 3.70-3.33 (m, dimethyl-7-oxo-1H- 7 H), 3.10-2.75 (m, 6 H), 2.20-2.00 (m, 1 H), pyrrolo[2,3-c]pyridine- 1.85-1.40 (m, 5 H), 1.38-1.10 (m, 7 H) 4-carboxamide 184 N-[2-(1-cyclobutyl-4- ¹H NMR (400 MHz, CD₃OD): δ 8.48 (s, 1 H), 371 piperidyl)ethyl]-N,6- 7.39-7.38 (m, 2 H), 6.34 (d, J = 3.0 Hz, 1 H), dimethyl-7-oxo-1H- 3.84-3.32 (m, 7 H), 3.06 (s, 3 H), pyrrolo[2,3-c]pyridine- 2.82-2.52 (m, 2 H), 2.37-2.25 (m, 2 H), 2.19-2.10 (m, 2 4-carboxamide H), 2.08-1.96 (m, 2 H), 1.91-1.77 (m, 2 H), 1.73-1.51 (m, 4 H), 1.44-1.16 (m, 2 H). 185 N-[2-[1-(2- ¹H NMR (400 MHz, CD₃OD): δ 8.52 (s, 1 H), 375 methoxyethyl)-4- 7.39 (d, J = 2.8 Hz, 2 H), 6.34 (d, J = 2.0 Hz, 1 piperidyl]ethyl]-N,6- H), 3.76-3.44 (m, 8 H), 3.37 (s, 3 H), dimethyl-7-oxo-1H- 3.22-3.18 (m, 2 H), 3.06 (s, 3 H), 2.99-2.53 (m, 3 H), pyrrolo[2,3-c]pyridine- 2.25-1.90 (m, 1 H), 1.75-1.25 (m, 6 H). 4-carboxamide 186 N-[2-(1-cyclopropyl-4- ¹H NMR (400 MHz, DMSO-d6): δ 11.40 (s, 1 301 piperidyl)ethyl]-N,6- H), 8.86 (s, 1 H), 8.30 (s, 1 H), 8.22 (s, 1 H), dimethyl-7-oxo-1H- 4.03 (s, 3 H), 2.50 (q, J = 1.6 Hz, 2 H), 2.44 (s, pyrrolo[2,3-c]pyridine- 3 H), 1.05 (t, J = 7.6 Hz, 3 H). 4-carboxamide

Example 187 N-[[1-(cyclopentylmethyl)-4-piperidyl]methyl]-N,6-dimethyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carboxamide

Step 1:

tert-butyl 4-[[methyl-(6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carbonyl)amino]methyl]piperidine-1-carboxylate

HATU (4.4 g, 11.7 mmol) was added to a stirred mixture of 6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carboxylic acid (Intermediate C) (1.5 g, 7.8 mmol), tert-butyl 4-(2-aminoethyl)piperidine-1-carboxylate (2.1 g, 9.4 mmol), and diisopropylethylamine (2.0 g, 15.6 mmol) in DMF (50 mL). After addition, the reaction mixture was stirred at room temperature for 2 h, at which time LCMS showed the completion of the reaction. The reaction mixture was diluted with ethyl acetate (200 mL), and then washed with water (50 mL), brine (20 mL×2), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (dichloromethane:methanol=10:1) to afford the title compound (2.3 g, 74.2% yield) as a white solid. LCMS M/Z (M+H) 402.9.

Step 2:

N,6-dimethyl-7-oxo-N-(4-piperidylmethyl)-1H-pyrrolo[2,3-c]pyridine-4-carboxamide hydrogen chloride

A mixture of tert-butyl 4-[[methyl-(6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carbonyl)amino]methyl]piperidine-1-carboxylate (2.3 g, 5.7 mmol) in 4 N hydrogen chloride/ethyl acetate (20 mL) was stirred at room temperature for 2 h. The solvent was evaporated to give the crude title compound (1.5 g, 88.2% yield) as a colorless oil. LCMS M/Z (M+H) 303.1.

Step 3:

N-[[1-(cyclopentylmethyl)-4-piperidyl]methyl]-N,6-dimethyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carboxamide

Sodium triacetoxyborohydride (112 mg, 0.53 mmol) was added to a stirred mixture of N,6-dimethyl-7-oxo-N-(piperidin-4-ylmethyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-carboxamide hydrochloride (80 mg, 0.24 mmol), cyclopentanecarbaldehyde (39 mg, 0.40 mmol) in dichloromethane (10 mL). After addition, the reaction mixture was stirred at room temperature for 20 h, at which time LCMS showed the completion of the conversion. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC, acetonitrile: water (10 nM ammonia), 55%-85%, to give the title compound (8.7 mg, 7.8% yield) as a white solid. ¹H NMR (400 MHz, CD₃OD): δ 7.40 (s, 2 H), 6.35 (d, J=2.4 Hz, 1 H), 3.67 (s, 3 H), 3.50-3.45 (m, 2 H), 2.92 (s, 3 H), 2.91-2.89 (m, 2 H), 2.39-2.32 (m, 2 H), 2.20-2.11 (m, 4 H), 1.81-1.58 (m, 10 H), 1.19-1.12 (m, 2 H). LCMS M/Z (M+H) 385.20.

The following compounds were prepared in a similar fashion to Example 187.

Examples 188-206

Example Compound Name NMR m/z 188 N,6-dimethyl-N-[(1- ¹H NMR (400 MHz, DMSO-d6): δ 12.14 (s, 1 317 methyl-4- H), 7.40 (s, 1 H), 7.33 (d, J = 2.4 Hz, 1 H), piperidyl)methyl]-7-oxo- 6.17 (d, J = 2.4 Hz, 1 H), 3.52 (s, 3 H), 1H-pyrrolo[2,3- 3.32-3.30 (m, 2 H), 2.98 (s, 3 H), 2.75-2.70 (m, 2 c]pyridine-4- H), 2.10 (s, 3 H), 1.78-1.75 (m, 3 H), carboxamide 1.69-1.45 (m, 3 H), 1.20-0.80 (m, 2 H) 189 N-[(1-cyclobutyl-4- ¹H NMR (400 MHz, CD₃OD): δ 8.50 (s, 1 H), 357 piperidyl)methyl]-N,6- 7.41-7.39 (m, 2 H), 6.34 (d, J = 2.8 Hz, 1 H), dimethyl-7-oxo-1H- 3.66 (s, 3 H), 3.53-3.34 (m, 5 H), 3.09 (s, 3 pyrrolo[2,3-c]pyridine-4- H), 2.75-2.65 (m, 2 H), 2.40-1.75 (m, 9 H), carboxamide 1.70-1.45 (m, 2H) 190 N-[(1-isopropyl-4- ¹H NMR (400 MHz, CD₃OD): δ 8.52 (s, 1 H), 345 piperidyl)methyl]-N,6- 7.40-7.38 (m, 2 H), 6.33 (d, J = 2.8 Hz, 1 H), dimethyl-7-oxo-1H- 3.64 (s, 3 H), 3.53-3.34 (m, 4 H), 3.08 (s, 3 pyrrolo[2,3-c]pyridine-4- H), 3.06-2.88 (m, 2 H), 2.30-1.80 (m, 2 H), carboxamide 1.60 (m, 2 H), 1.40-1.25 (m, 6 H) 191 N-[(1-ethyl-4- ¹H NMR (400 MHz, DMSO-d6): δ 12.07 (s, 1 331 piperidyl)methyl]-N,6- H), 8.24 (s, 1 H), 7.91 (t, J = 5.2 Hz, 1 H), dimethyl-7-oxo-1H- 7.77 (s, 1 H), 7.30 (s, 1 H), 6.67 (s, 1 H), pyrrolo[2,3-c]pyridine-4- 3.52 (s, 3 H), 3.26-3.23 (m, 2 H), 2.91 (d, J = 11.2 Hz, carboxamide 2 H), 2.52 (s, 3 H), 2.34-2.31 (m, 1 H), 1.96 (t, J = 10.8 Hz, 2 H), 1.69 (d, J = 11.6 Hz, 2 H), 1.46-1.40 (m, 2 H), 1.21-1.14 (m, 2 H), 0.99 (t, J = 7.2 Hz, 3 H). 192 N-[(1-cyclopropyl-4- ¹H NMR (400 MHz, DMSO-d6): δ 11.90 (s, 1 343 piperidyl)methyl]-N,6- H), 7.16 (s, 1 H), 7.10 (s, 1 H), 5.95 (s, 1 H), dimethyl-7-oxo-1H- 3.30 (s, 3 H), 3.07-3.00 (m, 3 H), 2.71 (s, 3 pyrrolo[2,3-c]pyridine-4- H), 2.69-2.64 (m, 2 H), 1.88-1.65 (m, 2 H), carboxamide 1.49-1.26 (m, 5 H), 0.16-0.13 (m, 2 H), 0.04-0.01 (m, 2 H). 193 N-[[1-(2-methoxyethyl)- ¹H NMR (400 MHz, DMSO-d6): δ 12.08 (s, 1 361 4-piperidyl]methyl]-N,6- H), 7.91-7.85 (m, 1 H), 7.79 (s, 1 H), 7.31 (d, dimethyl-7-oxo-1H- J = 2.8 Hz, 1 H), 6.69 (d, J = 2.8 Hz, 1 H), pyrrolo[2,3-c]pyridine-4- 3.54 (s, 3 H), 3.40 (t, J = 6.4 Hz, 2H), carboxamide 3.26 (d, J = 5.2 Hz, 2 H), 3.21 (s, 3 H), 2.82 (d, J = 11.6 Hz, 2H), 2.41 (t, J = 6.4 Hz, 2 H), 1.89 (t, J = 10.8 Hz, 2 H), 1.65 (d, J = 11.6 Hz, 2 H), 1.47-1.41 (m, 2 H), 1.24-1.21 (m, 1 H), 1.18-1.09 (m, 2 H). 194 N-[(1-benzyl-4- ¹H NMR (400 MHz, CD₃OD): δ 7.40 (s, 1 H), 393 piperidyl)methyl]-N,6- 7.39 (s, 1 H), 7.31-7.28 (m, 5 H), 6.34 (d, J = 2.4 Hz, dimethyl-7-oxo-1H- 1 H), 3.67 (s, 3 H), 3.52-3.50 (m, 4 pyrrolo[2,3-c]pyridine-4- H), 3.06 (s, 3 H), 2.93-2.85 (m, 2 H), carboxamide 2.10-2.04 (m, 2 H), 1.67-1.02 (m, 5 H). 195 N,6-dimethyl-N-[[1-(o- ¹H NMR (400 MHz, CD₃OD): δ 7.40-7.38 (m, 407 tolylmethyl)-4- 2H), 7.23-7.15 (m, 4 H), 6.34 (d, J = 2.8 Hz, piperidyl]methyl]-7-oxo- 1 H), 3.66 (s, 3 H), 3.49-3.45 (m, 4 H), 1H-pyrrolo[2,3- 3.08 (s, 3 H), 2.96-2.93 (m, 2 H), 2.35 (s, 3 H), c]pyridine-4- 2.06-2.00 (m, 2 H), 1.76-1.24 (m, 5 H). carboxamide 196 N,6-dimethyl-7-oxo-N- ¹H NMR (400 MHz, DMSO-d6): δ 12.13 (s, 1 407 [[1-(p-tolylmethyl)-4- H), 7.38 (s, 1 H), 7.32 (d, J = 2.4 Hz, 1 H), piperidyl]methyl]-1H- 7.12-7.08 (m, 4 H), 6.17 (d, J = 3.2 Hz, 1 H), pyrrolo[2,3-c]pyridine-4- 3.52 (s, 3 H), 3.33-3.30 (m, 4 H), 2.93 (s, 3 carboxamide H), 2.74-2.71 (m, 2 H), 2.26 (s, 3 H), 1.88-1.85 (m, 2 H), 1.66-1.54 (m, 3 H), 1.09-1.05 (m, 2 H). 197 N,6-dimethyl-7-oxo-N- ¹H NMR (400 MHz, DMSO-d6): δ 12.09 (s, 1 406 [[1-(1-phenylethyl)-4- H), 7.33 (s, 1 H), 7.27-7.22 (m, 6 H), 6.12 (d, piperidyl]methyl]-1H- J = 2.4 Hz, 1 H), 3.48 (s, 3 H), 3.27-3.25 (m, pyrrolo[2,3-c]pyridine-4- 2 H), 2.86 (s, 3 H), 2.65-2.63 (m, 1 H), carboxamide 2.50-2.47 (m, 4 H), 1.83-1.80 (m, 3 H), 1.77-1.56 (m, 2 H), 1.22-1.20 (m, 3 H) 198 N-[[1-[(2- ¹H NMR (400 MHz, DMSO-d6): δ 12.13 (s, 1 427 chlorophenyl)methyl]-4- H), 7.44-7.39 (m, 3 H), 7.32-7.24 (m, 3 H), piperidyl]methyl]-N,6- 6.18 (d, J = 2.4 Hz, 1 H), 3.53 (s, 5 H), dimethyl-7-oxo-1H- 2.94 (s, 3 H), 2.78-2.75 (m, 2 H), 2.50-2.47 (m, 2 pyrrolo[2,3-c]pyridine-4- H), 2.02-1.98 (m, 2 H), 1.70-1.57 (m, 3 H), carboxamide 1.24-1.20 (m, 2 H). 199 N-[[1-[(3- ¹H NMR (400 MHz, CD₃OD): δ 427 chlorophenyl)methyl]-4- 7.40-7.29 (m, 6 H), 6.34 (d, J = 2.4 Hz, 1 H), 3.67 (s, 3 piperidyl]methyl]-N,6- H), 3.52-3.42 (m, 4 H), 3.08 (s, 3 H), dimethyl-7-oxo-1H- 2.90-2.86 (m, 2 H), 2.04-1.98 (m, 2 H), pyrrolo[2,3-c]pyridine-4- 1.77-1.63 (m, 5 H). carboxamide 200 N-[[1-[(4- ¹H NMR (400 MHz, DMSO-d6): δ 12.08 (s, 1 427 chloropbenyl)methyl]-4- H), 7.34-7.25 (m, 6 H), 6.12 (s, 1 H), 3.48 (s, piperidyl]methyl]-N,6- 3 H), 3.36-3.31 (m, 2 H), 2.89 (s, 3 H), dimethyl-7-oxo-1H- 2.70-2.68 (m, 2 H), 2.50-2.47 (m, 2 H), pyrrolo[2,3-c]pyridine-4- 1.86-1.84 (m, 2 H), 1.63-1.51 (m, 3 H), 1.13-1.10 (m, 2 carboxamide H). 201 N-[[1-[(2- ¹H NMR (400 MHz, DMSO-d6): δ 12.12 (s, 1 411 fluorophenyl)methyl]-4- H), 7.38-7.28 (m, 4 H), 7.17-7.11 (m, 2 H), piperidyl]methyl]-N,6- 6.17 (s, 1 H), 3.52-3.48 (m, 5 H), 2.93 (s, 3 dimethyl-7-oxo-1H- H), 2.75-2.71 (m, 2 H), 2.50-2.47 (m, 2 H), pyrrolo[2,3-c]pyridine-4- 1.97-1.92 (m, 2 H), 1.66-1.56 (m, 3 H), carboxamide 1.10-1.08 (m, 2 H). 202 N-[[1-[(3- ¹H NMR (400 MHz, DMSO-d6): δ 12.13 (s, 1 411 fluorophenyl)methyl]-4- H), 7.39-7.31 (m, 3 H), 7.12-7.07 (m, 3 H), piperidyl]methyl]-N,6- 6.17 (s, 1 H), 3.52 (s, 3 H), 3.44 (s, 2 H), dimethyl-7-oxo-1H- 2.93 (s, 3 H), 2.76-2.71 (m, 2 H), 2.50-2.47 (m, 2 pyrrolo[2,3-c]pyridine-4- H), 1.91-1.89 (m, 2 H), 1.68-1.56 (m, 3 H), carboxamide 1.18-1.15 (m, 2 H). 203 N-[[1-[(4- ¹H NMR (400 MHz, DMSO-d6): δ 12.13 (s, 1 411 fluorophenyl)methyl]-4- H), 7.38-7.29 (m, 4 H), 7.13-7.09 (m, 2 H), piperidyl]methyl]-N,6- 6.17 (s, 1 H), 3.52 (s, 3 H), 3.40 (s, 2H), dimethyl-7-oxo-1H- 2.93 (s, 3 H), 2.74-2.71 (m, 2 H), 2.50-2.47 (m, 2 pyrrolo[2,3-c]pyridine-4- H), 1.88-1.82 (m, 2 H), 1.66-1.57 (m, 3 H), carboxamide 1.15-1.08 (m, 2 H). 204 N,6-dimethyl-N-[[1-(m- ¹H NMR (400 MHz, CD₃OD): δ 12.13 (s, 1 406 tolylmethyl)-4- H), 7.38 (s, 1 H), 7.32 (s, 1 H), 7.19-7.15 (m, piperidyl]methyl]-7-oxo- 1 H), 7.06-7.02 (m, 3 H), 6.17 (s, 1 H), 1H-pyrrolo[2,3- 3.52 (s, 3 H), 3.36 (s, 2 H), 2.93 (s, 3 H), c]pyridine-4- 2.74-2.71 (m, 2 H), 2.27 (s, 3 H), 1.88-1.85 (m, 2 H), carboxamide 1.67-1.55 (m, 3 H), 1.15-1.08 (m, 2 H). 205 N-[(1-cyclopentyl-4- ¹H NMR (400 MHz, CD₃OD): δ 7.40 (s, 2 H), 371 piperidyl)methyl]-N,6- 6.35 (d, J = 3.2 Hz, 1 H), 3.67 (s, 3 H), dimethyl-7-oxo-1H- 3.49-3.45 (m, 2 H), 3.09-2.93 (m, 5 H), pyrrolo[2,3-c]pyridine-4- 2.55-2.52 (m, 1 H), 1.91-1.40 (m, 15 H). carboxamide 206 N-[[1- ¹H NMR (400 MHz, CD₃OD): δ 7.43 (s, 1 H), 399 (cyclohexylmethyl)-4- 7.42 (s, 1 H), 6.36 (s, 1 H), 3.68 (s, 3 H), piperidyl]methyl]-N,6- 3.50-3.45 (m, 4 H), 3.11 (s, 3 H), dimethyl-7-oxo-1H- 2.90-2.85 (m, 4 H), 2.12-1.71 (m, 10 H), 1.37-1.22 (m, pyrrolo[2,3-c]pyridine-4- 4 H), 1.10-1.06 (m, 2 H). carboxamide

Example 207 N-(1-isobutyl-4-piperidyl)-N,6-dimethyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carboxamide

Step 1:

N,6-dimethyl-7-oxo-N-(4-piperidyl)-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridine-4-carboxamide hydrochloride

To a 40 mL vial was added 6-methyl-7-oxo-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridine-4-carboxylic acid (Intermediate E, 1.24 g, 2.6 mmol) N,N-dimethylformamide (10 mL), HATU (1.1 g, 2.9 mmol), and triethylamine (1.09 mL 7.8 mmol). The reaction was stirred for 15 minutes. Tert-butyl 4-(methylamino)piperidine-1-carboxylate (1.5 equiv., 3.9 mmol) was then added, and the reaction was shaken at room temperature for 4 h. The reaction was then diluted with ethyl acetate, and then washed with water. The aqueous solution was further extracted 2 times with ethyl acetate. The combined organic extracts were dried over sodium sulfate, and concentrated under reduced pressure to affort 1.09 g of crude product. The crude material was up in methanol (20 mL) and 4N hydrogen chloride in dioxane (20 mL). The reaction was stirred at room temperature for 1 h and then concentrated under reduced pressure to yield 965 mg of product that was 80% pure by LCMS. LCMS M/Z (M+H) 443. This material was used without further purification.

Step 2:

N-(1-isobutyl-4-piperidyl)-N,6-dimethyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carboxamide

MP-Cyanoborobydride (0.2 g, 2.39 mmol/g, 0.48 mmol) was added to a mixture of N,6-dimethyl-7-oxo-N-(4-piperidyl)-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridine-4-carboxamide hydrochloride (75 mg, 0.16 mmol), methanol (0.75 mL), 1,2-dichloroethane (0.75 mL), isobutyraldehyde (23 mg, 0.32 mmol) and triethylamine (0.043 mL, 0.31 mmol). The reaction was shaken at room temperature overnight and the mixture was filtered, washing the resin with methanol. The filtrate was concentrated under reduced pressure and the residue was purified by preperative HPLC (5-85% MeOH/0.1% NH4OH in H2O) to give N-(1-isobutyl-4-piperidyl)-N,6-dimethyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carboxamide (11.2 mg, 20%). ¹H NMR (400 MHz, DMSO-d6) δ 12.12 (s, 2H), 7.39-7.29 (m, 3H), 6.18 (d, J=2.8 Hz, 2H), 3.72-3.67 (m, 1H), 3.52 (s, 5H), 2.91-2.78 (m, 2H), 2.28-2.23 (m, 3H), 2.05-1.95 (m, 3H), 1.84-1.65 (m, 4H), 1.63-1.56 (m, 2H), 0.88-0.80 (m, 6H). LCMS M/Z (M+H) 345.

The following compounds were prepared in a similar fashion to Example 207.

Examples 208-209

Example Compound Name NMR m/z 208 N-[1- ¹H NMR (400 MHz, DMSO-d₆) δ 12.12 (s, 1H), 343 (cyclopropylmethyl)- 7.39-7.29 (m, 2H), 6.19 (d, J = 2.7 Hz, 1H), 4-piperidyl]-N,6- 3.52 (s, 3H), 3.30 (s, 31H), 3.03-2.98 (m, 2H), 2.83 (s, dimethyl-7-oxo-1H- 3H), 2.29-2.24 (m, 2H), 1.86-1.81 (m, 2H), pyrrolo[2,3- 1.81-1.73 (m, 1H), 1.60 (d, J = 10.8 Hz, 2H), c]pyridine-4- 0.80 (d, J = 8.1 Hz, 1H), 0.49-0.39 (m, 2H), carboxamide 0.13-0.02 (m, 2H). 209 Trans-N-(3-fluoro-1- ¹H NMR (400 MHz, DMSO-d₆) δ 12.07 (s, 1H), 335 isopropyl-4- 8.02 (d, J = 8.3 Hz, 1H), 7.80 (s, 1H), piperidyl)-6-methyl- 7.37-7.26 (m, 1H), 6.69 (dd, J = 2.8, 1.6 Hz, 1H), 4.52 (dtd, J = 50.3, 7-oxo-1H- 9.6, 5.0 Hz, 1H), 3.91 (d, J = 7.1 Hz, 1H), pyrrolo[2,3- 3.56 (s, 3H), 3.21-3.06 (m, 1H), 2.94-2.60 (m, c]pyridine-4- 2H), 2.29-2.08 (m, 2H), 1.89 (d, J = 14.6 Hz, carboxamide 1H), 1.50 (tt, J = 12.5, 6.1 Hz, 1H), 0.98 (dd, J = 6.6, 3.3 Hz, 6H).

Example 210 N-(1,4-dimethyl-4-piperidyl)-6-methyl-7-ox-1H-pyrrolo[2,3-c]pyridine-4-carboxamide

Step 1:

tert-butyl 4-(((benzyloxy)carbonyl)amino)-4-methylpiperidine-1-carboxylate

A mixture of 1-(tert-butoxycarbonyl)-4-methylpiperidine-4-carboxylic acid (Intermediate C, 5.0 g, 20.5 mmol), triethylamine (4.3 mL, 30.8 mmol) and diphenylphosphoryl azide (6.0 mL, 29.8 mmol) in toluene (100 mL) was stirred at room temperature for 1 h. Benzyl alcohol (5.4 mL, 51.3 mmol) was added into the reaction mixture and the reaction mixture was heated at 80° C. for 18 h, at which time TLC showed the completion of the reaction. The solvent was evaporated and the residue was dissolved in ethyl acetate (100 mL). The solution was washed with water (30 mL×2), dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate=3:1) to give the title compound (1.8 g, 25.2% yield) as colorless oil. LCMS M/Z (M+H) 349.1.

Step 2:

benzyl (4-methylpiperidin-4-yl)carbamate hydrochloride

tert-Butyl 4-(((benzyloxy)carbonyl)amino)-4-methylpiperidine-1-carboxylate (1.3 g, 3.73 mmol) in dioxane (30 mL) was treated with hydrogen chloride (4 N in dioxane, 10 mL). The reaction mixture was stirred at room temperature for 2 h, at which time TLC indicated that the reaction had gone to completion. The mixture was concentrated under reduced pressure to give the crude title compound (1.0 g, 100% yield) as colorless oil. This material was used into next step without further treatment. LCMS M/Z (M+H) 248.9.

Step 3:

benzyl (1,4-dimethylpiperidin-4-yl)carbamate

A mixture of benzyl (4-methylpiperidin-4-yl)carbamate hydrochloride (650 mg, 2.3 mmol), formaldehyde (aq. 35-40%, 1 mL) and sodium cyanoborohydride (289 mg, 4.6 mmol) in methanol (30 mL) was stirred at 90° C. for 3 h, at which time LCMS indicated the reaction had gone to completion. The reaction was quenched by addition of saturated aqueous ammonium chloride (5 mL). This mixture was adjusted to pH 8-9 using saturated aqueous sodium bicarbonate and the resulting mixture was extracted with ethyl acetate (3×30 mL). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure to give the crude title compound (300 mg, 49.7% yield) as colorless oil. LCMS M/Z (M+H) 263.1.

Step 4:

1,4-dimethylpiperidin-4-amine di-hydrochloride

A mixture of benzyl (1,4-dimethylpiperidin-4-yl)carbamate (300 mg, 1.16 mmol) and palladium on charcoal (50 mg) in methanol (50 mL) and concentrated hydrochloric acid (one drop) was stirred under a hydrogen atmosphere (balloon) for 18 h, at which time LCMS indicated the reaction had gone to completion. The mixture was filtered through a short pad of Celite and rinsed with methanol (10 mL). The combined organic filtrates were concentrated under reduced pressure to give the crude title compound (100 mg, 43% yield) as light yellow oil. This crude material was used directly in the next step.

Step 5

N-(1,4-dimethyl-4-piperidyl)-6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carboxamide

HATU (305 mg, 0.80 mmol) was added to a mixture of 6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carboxylic acid (Intermediate C) (141 mg, 0.73 mmol), 1,4-dimethylpiperidin-4-amine di-hydrochloride (189 mg, 1.47 mmol), and diisopropylethylamine (300 mg, 2.32 mmol) in DMF (2 mL). The resulting mixture was stirred at room temperature for 2 h, at which time LCMS indicated that the reaction had gone to completion. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (2×20 mL). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC, acetonitrile: water (10 nM ammonia bicarbonate), 0%-30%, to give the title compound (49 mg, 22.3% yield) as a white solid. ¹H NMR (400 MHz, CD₃OD): δ 7.68 (s, 1 H), 7.37 (d, J=2.8 Hz, 1 H), 6.68 (d, J=2.8 Hz, 1 H), 3.67 (s, 3 H), 2.69-2.60 (m, 2 H), 2.46-2.32 (m, 7 H), 1.8-1.65 (m, 2 H), 1.48 (s, 3 H). LCMS M/Z (M+H) 303.1.

Example 211 N-[(1,4-dimethyl-4-piperidyl)methyl]-6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carboxamide

Step 1:

tert-butyl 4-cyano-4-methylpiperidine-1-carboxylate

Under nitrogen protection, LDA (IM in THF, 26.2 mL, 26.2 mmol) was added dropwise to a stirred and cooled (−78° C.) solution of tert-butyl 4-cyanopiperidine-1-carboxylate (5.0 g, 23.8 mmol) in THF (100 mL). After addition, the reaction mixture was stirred at −78° C. for 1 h, and then methyl iodide (1.48 mL, 23.8 mmol) was added dropwise. The resulting mixture was allowed warm to room temperature and stirring was continued for 2 h. The reaction was quenched by addition of saturated aqueous ammonium chloride (50 mL), and extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate 4:1) to give the title compound (4.3 g, 81% yield) as light yellow oil. ¹H NMR (400 MHz, CDCl₃): δ 4.10-3.95 (m, 2 H), 3.10-2.95 (m, 2 H), 1.90-1.85 (d, J=12 Hz, 2 H), 1.45-1.32 (m, 14 H).

Step 2:

tert-butyl 4-(aminomethyl)-4-methylpiperidine-1-carboxylate

Raney-Ni (3.0 g) was carefully added to a solution of tert-butyl 4-cyano-4-methylpiperidine-1-carboxylate (4.3 g, 19.2 mmol) in methanol under nitrogen. After addition, the mixture was stirred under hydrogen (50 psi) for 2 h at room temperature. The resulting mixture was filtered through a short pad of Celite using dichloromethane to rinse. The filtrate was concentrated under reduced pressure to give the title compound (4.0 g, 91.5% yield) as light brown oil. This crude material was used directly in the next step. LCMS M/Z (M+H) 229.1.

Step 3:

tert-butyl 4-methyl-4-[[(6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carbonyl)amino]methyl]piperidine-1-carboxylate

HATU (294 mg, 0.8 mmol) was added to the mixture of 6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-carboxylic acid (Intermediate C) (135 mg, 0.7 mmol), tert-butyl 4-(aminomethyl)-4-methylpiperidine-1-carboxylate (160 mg, 0.7 mmol), and diisopropylethylamine (181 mg, 1.4 mmol) in DMF (3 mL). After addition, the reaction mixture was stirred at room temperature for 2 h, at which time LCMS indicated that the reaction had gone to completion. The mixture was quenched by addition of water (5 mL) and extracted with ethyl acetate (2×10 mL). The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude title compound (275 mg, 94% yield) as light brown oil. This crude material was used directly in the next step. LCMS M/Z (M+H) 402.9.

Step 4:

N-((1,4-dimethylpiperidin-4-yl)methyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-carboxamide

tert-Butyl 4-methyl-4-[[(6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carbonyl)amino]methyl]piperidine-1-carboxylate (275 mg, 0.7 mmol) was treated with 4N hydrogen chloride in ethyl acetate (10 mL) for 1 h at room temperature. The mixture was concentrated under reduced pressure and the residue was mixed with paraformaldehyde (18 mg, 0.6 mmol), triethylamine (90 mg, 0.9 mmol), and methanol (5 mL). The resulting mixture was heated at 90° C. for 2 h and then cooled to 0° C. Sodium borohydride (45 mg, 1.2 mmol) was added to the mixture in one portion and stirring was continued for 30 min at room temperature, at which time LCMS indicated the reaction had gone to completion. The mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (acetonitrile: water (0.3% formic acid), 1%-30%) to give the title compound (30.1 mg, 32.3%) as a white solid. ¹H NMR (400 MHz, CD₃OD): δ 7.78 (s, 1 H), 7.38 (d, J=2.8 Hz, 1 H), 6.73 (d, J=2.8 Hz, 1 H), 3.67 (s, 3 H), 3.49-3.20 (m, 6 H), 2.87 (s, 3 H), 1.83-1.81 (m, 2 H), 1.68-1.65 (m, 2 H), 1.13 (s, 3 H). LCMS M/Z (M+H) 317.2.

The following compound was prepared in a similar fashion to Example 211.

Examples 212

Example Compound Name NMR m/z 212 N-[(1-isopropyl-4- ¹H NMR (400 MHz, CD₃OD): δ 8.34 (s, 1 H), 345 methyl-4- 7.76 (s, 1 H), 7.38 (d, J = 2.8 Hz, 1 H), 6.73 (d, piperidyl)methyl]-6- J = 2.4 Hz, 1 H), 3.67 (s, 3 H), 3.50-3.10 (m, 7 methyl-7-oxo-1H- H), 1.86-1.83 (m, 2 H), 1.71-1.67 (m, 2 H), pyrrolo[2,3-c]pyridine- 1.37 (d, J = 8.0 Hz, 6 H), 1.12 (s, 3H). 4-carboxamide

Example 213 N-[1-[(4-cyanophenyl)methyl]-4-piperidyl]-N,6-dimethyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carboxamide

Step 1:

N,6-dimethyl-7-oxo-N-(4-piperidyl)-1H-pyrrolo[2,3-c]pyridine-4-carboxamide hydrochloride

To a 40 mL vial was added 6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carboxylic acid (Intermediate C, 690 mg. 3.6 mmol) followed by N,N-dimethylformamide (10 mL), HATU (1.67 g, 4.4 mmol), triethylamine (2.02 mL, 14.5 mmol) and tert-butyl 4-(methylamino)piperidine-1-carboxylate (900 mg., 4.2 mmol). The reaction was capped and shaken at room temperature for 2 h. The resulting precipitate was collected by filtration, washed with ethyl acetate, and dried to afford the desired boc-protected amine intermediate (513 mg, 36%). This material was suspended in methanol (4 mL) and hydrogen chloride (4 N in dioxane, 4 mL) was added. The reaction was shaken at room temperature for 1 h and then concentrated under reduced pressure to afford N,6-dimethyl-7-oxo-N-(4-piperidyl)-1H-pyrrolo[2,3-c]pyridine-4-carboxamide hydrochloride (425 mg, 36%). This material was used directly in the next step.

Step 2:

N-[1-[(4-cyanophenyl)methyl]-4-piperidyl]-N,6-dimethyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carboxamide

To a 4 mL vial was added N,6-dimethyl-7-oxo-N-(4-piperidyl)-1H-pyrrolo[2,3-c]pyridine-4-carboxamide hydrochloride (43 mg, 0.13 mmol) followed by N,N-dimethylformamide (0.5 mL), diisopropylethylamine (3 equiv., 0.40 mmol), and 4-(bromomethyl)benzonitrile (1.1 equiv., 0.15 mmol). The reaction was capped and shaken at 50° C. overnight. After cooling, the mixture was diluted with dichloromethane, washed with water and concentrated under reduced pressure. The residue was purified by preparative HPLC (5-85% MeOH/0.1% NH4OH in H2O) to yield N-[1-[(4-cyanophenyl)methyl]-4-piperidyl]-N,6-dimethyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carboxamide (25 mg, 48%). 1H NMR (400 MHz, DMSO-d6) δ 12.11 (s, 1H), 7.82-7.74 (m, 2H), 7.50 (dd, J=8.2, 3.4 Hz, 2H), 7.39-7.28 (m, 2H), 6.18 (d, J=2.8 Hz, 1H), 4.01 (s, 1H), 3.53 (d, J=5.4 Hz, 5H), 2.83 (s, 5H), 1.99 (d, J=15.0 Hz, 2H), 1.89-1.70 (m, 2H), 1.61 (d, J=11.5 Hz, 2H). LCMS M/Z (M+H) 404.

The following compounds were prepared in a similar fashion to Example 213.

Examples 214-243

Example Compound Name NMR m/z 214 N,6-dimethyl-7-oxo-N-[1- ¹H NMR (400 MHz, DMSO-d₆) δ 393 (1-phenylethyl)-4- 7.41-7.12 (m, 7H), 6.16 (d, J = 2.7 Hz, 1H), 3.51 (s, piperidyl]-1H- 3H), 3.48-3.37 (m, 1H), 3.09-2.59 (m, pyrrolo[2,3-c]pyridine-4- 4H), 1.94-1.59 (m, 6H), 1.33-1.23 (m, carboxamide 3H). 215 N-[1-[(2- ¹H NMR (400 MHz, DMSO-d₆) δ 12.12 (s, 404 cyanophenyl)methyl]-4- 1H), 7.80 (ddd, J = 8.0, 4.0, 1.3 Hz, 1H), piperidyl]-N,6-dimethyl- 7.72-7.62 (m, 1H), 7.60-7.52 (m, 1H), 7-oxo-1H-pyrrolo[2,3- 7.51-7.41 (m, 1H), 7.39-7.29 (m, 2H), 6.19 (d, J = 2.7 Hz, c]pyridine-4-carboxamide 1H), 3.61 (d, J = 5.8 Hz, 2H), 3.52 (s, 3H), 2.82 (s, 5H), 2.12-2.01 (m, 2H), 1.86-1.72 (m, 2H), 1.66-1.58 (m, 2H). 216 N-[1-[(2- ¹H NMR (400 MHz, DMSO-d₆) δ 12.11 (s, 397 fluorophenyl)methyl]-4- 1H), 7,44-7.25 (m, 4H), 7.21-7.09 (m, piperidyl]-N,6-dimethyl- 2H), 6.18 (d, J = 2.7 Hz, 1H), 3.99 (s, 1H), 7-oxo-1H-pyrrolo[2,3- 3.54-3.44 (m, 5H), 2.92-2.80 (m, 5H), c]pyridine-4-carboxamide 2.01-1.93 (m, 3H), 1.87-1.69 (m, 3H), 1.65-1.56 (m, 2H). 217 N-(1-isopentyl-4- ¹H NMR (400 MHz, DMSO-d₆) δ 12.11 (s, 359 piperidyl)-N,6-dimethyl- 1H), 7.38-7.28 (m, 2H), 6.18 (t, J = 2.1 Hz, 7-oxo-1H-pyrrolo[2,3- 1H), 3.96 (s, 1H), 3.52 (s, 3H), 3.30 (d, J = 18.3 Hz, c]pyridine-4-carboxamide 1H), 2.89 (d, J = 8.6 Hz, 2H), 2.82 (s, 3H), 2.27-2.19 (m, 2H), 1.82-1.69 (m, 5H), 1.63-1.47 (m, 3H), 1.28 (q, J = 7.2 Hz, 2H), 0.85 (d, J = 6.6 Hz, 6H). 218 N,6-dimethyl-7-oxo-N-[1- ¹H NMR (400 MHz, DMSO-d₆) δ 12.11 (s, 393 (p-tolylmethyl)-4- 1H), 7.33 (d, J = 18.8 Hz, 2H), piperidyl]-1H- 7.19-7.07 (m, 4H), 6.18 (d, J = 2.7 Hz, 1H), 3.99 (s, pyrrolo[2,3-c]pyridine-4- 1H), 3.52 (s, 3H), 3.40-3.23 (m, 5H), carboxamide 2.88-2.80 (m, 5H), 2.27 (s, 3H), 1.91-1.86 (m, 2H), 1.85-1.71 (m, 2H), 1.63-1.55 (m, 2H). 219 N-[1- ¹H NMR (400 MHz, DMSO-d₆) δ 12.11 (s, 371 (cyclopentylmethyl)-4- 1H), 7.38-7.28 (m, 2H), 6.21-6.15 (m, piperidyl]-N,6-dimethyl- 1H), 3.96 (s, 1H), 3.52 (s, 3H), 2.91 (d, J = 8.9 Hz, 7-oxo-1H-pyrrolo[2,3- 2H), 2.82 (s, 3H), 2.17-2.10 (m, c]pyridine-4-carboxamide 2H), 2.08-1.95 (m, 1H), 1.83-1.72 (m, 5H), 1.69-1.41 (m, 9H), 1.21-1.08 (m, 2H). 220 N-[1-[(3- ¹H NMR (400 MHz, DMSO-d₆) δ 12.11 (s, 404 cyanophenyl)methyl]-4- 1H), 7.75-7.68 (m, 2H), 7.64 (d, J = 7.9 Hz, piperidyl]-N,6-dimethyl- 1H), 7.54 (t, J = 7.9 Hz, 1H), 7.39-7.28 (m, 7-oxo-1H-pyrrolo[2,3- 2H), 6.18 (d, J = 2.7 Hz, 1H), 4.01 (s, 1H), c]pyridine-4-carboxamide 3.51 (d, J = 6.5 Hz, 5H), 2.84 (s, 5H), 2.72 (d, J = 10.8 Hz, 0H), 1.99-1.94 (m, 2H), 1.88-1.75 (m, 2H), 1.65-1.57 (m, 2H). 221 N-[1-[(4- ¹H NMR (400 MHz, DMSO-d₆) δ 12.11 (s, 409 methoxyphenyl)methyl]- 1H), 7.38-7.28 (m, 2H), 7.21-7.14 (m, 4-piperidyl]-N,6- 2H), 6.91-6.83 (m, 2H), 6.18 (d, J = 2.7 Hz, dimethyl-7-oxo-1H- 1H), 3.98 (s, 1H), 3.73 (s, 3H), 3.52 (s, 3H), pyrrolo[2,3-c]pyridine-4- 3.35 (s, 2H), 2.82 (s, 5H), 1.87 (s, 2H), carboxamide 1.84-1.70 (m, 2H), 1.63-1.55 (m, 2H). 222 N-[1-[(3- ¹H NMR (400 MHz, DMSO-d₆) δ 12.11 (s, 409 methoxyphenyl)methyl]- 1H), 7.39-7.28 (m, 2H), 7.22 (t, J = 7.8 Hz, 4-piperidyl]-N,6- 1H), 6.89-6.76 (m, 3H), 6.18 (d, J = 2.8 Hz, dimethyl-7-oxo-1H- 1H), 4.00 (s, 1H), 3.73 (s, 3H), 3.52 (s, 3H), pyrrolo[2,3-c]pyridine-4- 3.40 (s, 2H), 2.83 (s, 5H), 1.94-1.89 (m, carboxamide 2H), 1.87-1.73 (m, 2H), 1.64-1.56 (m, 2H). 223 N-[1-[(2- ¹H NMR (400 MHz, DMSO-d₆) δ 12.12 (s, 413 chlorophenyl)methyl]-4- 1H), 7.52-7.43 (m, 1H), 7.45-7.23 (m, piperidyl]-N,6-dimethyl- 5H), 6.19 (d, J = 2.8 Hz, 1H), 4.07 (s, 1H), 7-oxo-1H-pyrrolo[2,3- 3.56-3.50 (m, 5H), 2.92-2.81 (m, 5H), c]pyridine-4-carboxamide 2.06-2.01 (m, 2H), 1.88-1.74 (m, 2H), 1.66-1.58 (m, 2H). 224 N-[1-[(3- ¹H NMR (400 MHz, DMSO-d₆) δ 12.11 (s, 413 chlorophenyl)methyl]-4- 1H), 7.39-7.21 (m, 8H), 6.18 (d, J = 2.8 Hz, piperidyl]-N,6-dimethyl- 1H), 4.00 (s, 1H), 3.52 (s, 3H), 3.44 (s, 3H), 7-oxo-1H-pyrrolo[2,3- 2.86-2.81 (m, 5H), 2.02-1.91 (m, 3H), c]pyridine-4-carboxamide 1.88-1.70 (m, 3H), 1.65-1.57 (m, 2H). 225 N-[1-(2-methoxyethyl)-4- ¹H NMR (400 MHz, DMSO-d₆) δ 12.11 (s, 347 piperidyl]-N,6-dimethyl- 1H), 7.38-7.28 (m, 2H), 6.18 (dd, J = 2.7, 7-oxo-1H-pyrrolo[2,3- 1.4 Hz, 1H), 3.96 (s, 1H), 3.52 (s, 3H), c]pyridine-4-carboxamide 3.39 (t, J = 5.8 Hz, 2H), 3.21 (s, 3H), 2.91 (d, J = 10.9 Hz, 2H), 2.82 (s, 3H), 2.53 (s, 1H), 2.43 (t, J = 5.9 Hz, 2H), 1.95-1.90 (m, 2H), 1.84-1.70 (m, 2H), 1.62-1.54 (m, 2H). 226 N-[1-(2- ¹H NMR (400 MHz, DMSO-d₆) δ 12.12 (s, 357 cyclopropylethyl)-4- 1H), 7.39-7.28 (m, 2H), 6.19 (t, J = 2.3 Hz, piperidyl]-N,6-dimethyl- 1H), 3.99 (s, 1H), 3.52 (s, 3H), 7-oxo-1H-pyrrolo[2,3- 2.96-2.91 (m, 2H), 2.82 (s, 4H), 2.35 (s, 2H), c]pyridine-4-carboxamide 1.90-1.85 (m, 2H), 1.83-1.75 (m, 2H), 1.65-1.60 (m, 2H), 1.36-1.26 (m, 2H), 0.70-0.57 (m, 1H), 0.42-0.31 (m, 2H), 0.01 (d, J = 5.9 Hz, 2H). 227 N-ethyl-N-(1-isopropyl-4- ¹H NMR (400 MHz, DMSO-d₆) δ 12.13 (s, 345 piperidyl)-6-methyl-7- 1H), 7.31 (d, J = 6.1 Hz, 2H), 6.15 (d, J = 2.8 Hz, oxo-1H-pyrrolo[2,3- 1H), 3.69 (s, 1H), 3.52 (s, 3H), c]pyridine-4-carboxamide 3.38-3.25 (m, 2H), 2.77 (d, J = 10.8 Hz, 2H), 2.63 (p, J = 6.6 Hz, 1H), 2.48 (s, 1H), 1.91 (s, 2H), 1.80-1.59 (m, 4H), 1.09 (t, J = 6.9 Hz, 3H), 0.89 (d, J = 6.5 Hz, 6H). 228 N-(3-isopropyl-3- ¹H NMR (400 MHz, DMSO-d₆) δ 12.05 (s, 315 azabicyclo[3.1.0]hexan-6- 1H), 7.93 (d, J = 4.2 Hz, 1H), 7.76 (s, 1H), yl)-6-methyl-7-oxo-1H- 7.33-7.27 (m, 1H), 6.72-6.66 (m, 1H), pyrrolo[2,3-c]pyridine-4- 3.53 (s, 3H), 3.06 (d, J = 8.7 Hz, 2H), 2.95 (d, J = 3.8 Hz, carboxamide 1H), 2.42-2.32 (m, 3H), 1.57 (s, 2H), 0.98 (d, J = 6.2 Hz, 6H). 229 N-[[1-(2- ¹H NMR (400 MHz, DMSO-d₆) δ 12.12 (s, 413 cyclohexylethyl)-4- 1H), 7.39 (s, 1H), 7.32 (t, J = 2.7 Hz, 1H), piperidyl]methyl]-N,6- 6.20-6.14 (m, 1H), 3.53 (s, 3H), dimethyl-7-oxo-1H- 3.32-3.27 (m, 2H), 2.93 (s, 3H), 2.80-2.75 (m, 2H), pyrrolo[2,3-c]pyridine-4- 2.26-2.17 (m, 2H), 1.81-1.76 (m, 2H), carboxamide 1.66-1.61 (m, 5H), 1.59-1.54 (m, 3H), 1.32-1.22 (m, 2H), 1.21-1.05 (m, 6H), 0.92-0.81 (m, 2H). 230 N,6-dimethyl-7-oxo-N- ¹H NMR (400 MHz, DMSO-d₆) δ 12.12 (s, 401 [[1-(tetrahydropyran-3- 1H), 7.39 (s, 1H), 7.35-7.29 (m, 1H), ylmethyl)-4- 6.17 (t, J = 2.4 Hz, 1H), 3.79-3.66 (m, 2H), piperidyl]methyl]-1H- 3.53 (s, 3H), 3.32-3.20 (m, 2H), 3.03-2.91 (m, pyrrolo[2,3-c]pyridine-4- 4H), 2.83-2.78 (m, 1H), 2.13-1.96 (m, carboxamide 2H), 1.84-1.76 (m, 1H), 1.74-1.66 (m, 5H), 1.56-1.39 (m, 4H), 1.14-1.06 (m, 4H). 231 N,6-dimethyl-7-oxo-N- ¹H NMR (400 MHz, DMSO-d₆) δ 12.12 (s, 387 [[1-(tetrahydrofuran-2- 1H), 7.39 (s, 1H), 7.32 (t, J = 2.5 Hz, 1H), ylmethyl)-4- 6.17 (dd, J = 2.9, 1.4 Hz, 1H), 3.86 (d, J = 9.1 Hz, piperidyl]methyl]-1H- 1H), 3.70 (q, J = 7.3 Hz, 1H), 3.53 (s, pyrrolo[2,3-c]pyridine-4- 4H), 3.30 (t, J = 4.9 Hz, 2H), 2.93 (s, 3H), carboxamide 2.79 (s, 1H), 2.33-2.27 (m, 2H), 1.97-1.81 (m, 3H), 1.81-1.68 (m, 2H), 1.66-1.61 (m, 2H), 1.55-1.50 (m, 2H), 1.49-1.35 (m, 2H), 1.07-1.02 (m, 3H). 232 N-[[1-(3-methoxypropyl)- ¹H NMR (400 MHz, DMSO-d₆) δ 12.12 (s, 375 4-piperidyl]methyl]-N,6- 1H), 7.39 (s, 1H), 7.35-7.29 (m, 1H), dimethyl-7-oxo-1H- 6.17 (d, J = 2.7 Hz, 1H), 3.53 (s, 3H), pyrrolo[2,3-c]pyridine-4- 3.32-3.25 (m, 2H), 3.19 (s, 3H), 2.93 (s, 3H), carboxamide 2.81-2.74 (m, 2H), 2.29-2.21 (m, 2H), 1.86-1.75 (m, 2H), 1.68-1.52 (m, 6H), 1.08-1.03 (m, 3H). 233 N-[[1-(cyclobutylmethyl)- ¹H NMR (400 MHz, DMSO-d₆) δ 12.12 (s, 371 4-piperidyl]methyl]-N,6- 1H), 7.38 (s, 1H), 7.35-7.29 (m, 1H), dimethyl-7-oxo-1H- 6.17 (d, J = 2.8 Hz, 1H), 3.53 (s, 3H), pyrrolo[2,3-c]pyridine-4- 3.32-3.25 (m, 2H), 2.93 (s, 3H), 2.71 (s, 2H), carboxamide 2.48-2.38 (m, 1H), 2.26 (d, J = 7.0 Hz, 2H), 1.96 (d, J = 9.8 Hz, 2H), 1.87-1.70 (m, 4H), 1.65-1.53 (m, 4H), 1.05-1.00 (m, 3H). 234 N,6-dimethyl-7-oxo-N- ¹H NMR (400 MHz, DMSO-d₆) δ 12.12 (s, 401 [[1-(tetrahydropyran-4- 1H), 7.39 (s, 1H), 7.32 (t, J = 2.6 Hz, 1H), ylmethyl)-4- 6.17 (t, J = 2.1 Hz, 1H), 3.79 (d, J = 10.8 Hz, piperidyl]methyl]-1H- 2H), 3.53 (s, 3H), 3.32-3.20 (m, 2H), pyrrolo[2,3-c]pyridine-4- 2.93 (s, 3H), 2.76 (s, 2H), 2.10-2.03 (m, 2H), carboxamide 1.83-1.75 (m, 2H), 1.70-1.65 (m, 2H), 1.59-1.50 (m, 4H), 1.13-1.02 (m, 4H). 235 N,6-dimethyl-7-oxo-N- ¹H NMR (400 MHz, DMSO-d₆) δ 12.12 (s, 401 [[1-(tetrahydropyran-2- 1H), 7.39 (s, 1H), 7.35-7.29 (m, 1H), ylmethyl)-4- 6.20-6.14 (m, 1H), 3.80 (d, J = 11.2 Hz, 1H), piperidyl]methyl]-1H- 3.53 (s, 3H), 3.38-3.22 (m, 2H), 2.93 (s, 3H), pyrrolo[2,3-c]pyridine-4- 2.82-2.77 (m, 2H), 2.33-2.23 (m, 1H), carboxamide 2.22-2.13 (m, 1H), 1.94-1.84 (m, 2H), 1.75-1.70 (m, 1H), 1.66-1.61 (m, 2H), 1.58-1.50 (m, 3H), 1.47-1.33 (m, 4H), 1.10-1.05 (m, 3H). 236 N,6-dimethyl-7-oxo-N- ¹H NMR (400 MHz, DMSO-d₆) δ 12.12 (s, 387 [[1-(tetrahydrofuran-3- 1H), 7.39 (s, 1H), 7.32 (t, J = 2.7 Hz, 1H), ylmethyl)-4- 6.18 (t, J = 2.2 Hz, 1H), 3.72-3.50 (m, 6H), piperidyl]methyl]-1H- 3.36-3.27 (m, 1H), 2.93 (s, 3H), 2.82 (s, pyrrolo[2,3-c]pyridine-4- 1H), 2.41-2.33 (m, 1H), 2.23-2.16 (m, carboxamide 2H), 1.92-1.79 (m, 4H), 1.68-1.63 (m, 1H), 1.57-1.52 (m, 2H), 1.51-1.41 (m, 2H), 1.08-1.03 (m, 3H). 237 N-cyclobutyl-N-(1- 1H NMR (400 MHz, DMSO-d6) δ 12.13 (d, J = 3.6 Hz, 371 isopropyl-4-piperidyl)-6- 1H), 7.34-7.25 (m, 2H), 6.14 (t, J = 2.3 Hz, methyl-7-oxo-1H- 1H), 4.13 (p, J = 8.8 Hz, 1H), pyrrolo[2,3-c]pyridine-4- 3.52 (s, 3H), 3.32 (s, 11H), 2.79 (d, J = 10.9 Hz, carboxamide 2H), 2.67 (p, J = 8.3, 7.4 Hz, 1H), 2.52-2.35 (m, 3H), 2.31 (d, J = 12.7 Hz, 2H), 2.11-1.90 (m, 4H), 1.52 (ddd, J = 38.7, 21.9, 9.9 Hz, 4H), 0.93 (d, J = 6.5 Hz, 6H). 238 Cis-N-(1-isopropyl-3- ¹H NMR (400 MHz, DMSO-d₆) δ 12.05 (s, 331 methyl-4-piperidyl)-6- 1H), 7.80 (s, 1H), 7.56-7.49 (m, 1H), methyl-7-oxo-1H- 7.31 (d, J = 2.8 Hz, 1H), 6.64 (d, J = 2.8 Hz, 1H), pyrrolo[2,3-c]pyridine-4- 4.01-3.90 (m, 1H), 3.56 (s, 3H), 2.65 (dq, J = 12.3, carboxamide 6.2, 5.7 Hz, 2H), 2.38-2.25 (m, 2H), 2.12-1.99 (m, 1H), 1.81-1.67 (m, 1H), 1.62-1.51 (m, 1H), 1.00-0.88 (m, 9H). 239 Trans-N-(1-isopropyl-3- ¹H NMR (400 MHz, DMSO-d₆) δ 12.04 (s, 331 methyl-4-piperidyl)-6- 1H), 7.81 (s, 1H), 7.74 (d, J = 8.6 Hz, 1H), methyl-7-oxo-1H- 7.33-7.28 (m, 1H), 6.68 (d, J = 2.7 Hz, 1H), pyrrolo[2,3-c]pyridine-4- 3.56 (s, 3H), 3.47 (dd, J = 13.7, 6.0 Hz, 1H), carboxamide 2.91-2.75 (m, 3H), 2.33-2.22 (m, 1H), 1.99 (t, J = 11.1 Hz, 1H), 1.86-1.67 (m, 2H), 1.60-1.46 (m, 1H), 1.01 (d, J = 6.5 Hz, 7H), 0.87 (d, J = 6.5 Hz, 3H). 240 Cis-N-(3-fluoro-1- ¹H NMR (400 MHz, DMSO-d₆) δ 12.06 (s, 335 isopropyl-4-piperidyl)-6- 1H), 7.92 (s, 1H), 7.84 (d, J = 7.6 Hz, 1H), methyl-7-oxo-1H- 7.34-7.28 (m, 1H), 6.72-6.66 (m, 1H), pyrrolo[2,3-c]pyridine-4- 4.77 (d, J = 49.9 Hz, 1H), 4.03-3.86 (m, 1H), carboxamide 3.55 (s, 3H), 3.09-2.99 (m, 1H), 2.85-2.67 (m, 2H), 2.50-2.42 (m, 1H), 2.25 (t, J = 11.3 Hz, 1H), 1.94-1.79 (m, 1H), 1.69-1.60 (m, 1H), 0.97 (dd, J = 6.6, 4.0 Hz, 6H). 241 N-(1-isopropylazepan-4- ¹H NMR (400 MHz, DMSO-d₆) δ 12.06 (s, 331 yl)-6-methyl-7-oxo-1H- 1H), 7.80 (s, 1H), 7.74 (d, J = 8.2 Hz, 1H), pyrrolo[2,3-c]pyridine-4- 7.34-7.28 (m, 1H), 6.67 (d, J = 2.7 Hz, 1H), carboxamide 4.09 (ddd, J = 13.2, 8.8, 4.6 Hz, 1H), 3.55 (s, 3H), 3.30 (d, J = 19.0 Hz, 1H), 2.92-2.77 (m, 1H), 2.68-2.50 (m, 4H), 1.93-1.81 (m, 1H), 1.80-1.60 (m, 4H), 1.60-1.47 (m, 1H), 0.94 (dd, J = 6.6, 2.1 Hz, 6H). 242 N-(8-isopropyl-8- ¹H NMR (400 MHz, DMSO-d₆) δ 12.09 (s, 357 azabicyclo[3.2.1]octan-3- 1H), 7.31 (d, J = 2.6 Hz, 2H), 6.17-6.11 (m, yl)-N,6-dimethyl-7-oxo- 1H), 4.48 (s, 1H), 3.52 (s, 3H), 3.47 (d, J = 9.1 Hz, 1H-pyrrolo[2,3- 2H), 2.75 (s, 3H), 2.28-2.08 (m, c]pyridine-4-carboxamide 3H), 1.92-1.82 (m, 2H), 1.51-1.41 (m, 2H), 1.38-1.27 (m, 2H), 0.90 (d, J = 5.7 Hz, 6H). 243 N-cyclopropyl-N-(1- ¹H NMR (400 MHz, DMSO-d₆) δ 12.02 (s, 357 isopropyl-4-piperidyl)-6- 1H), 7.45 (s, 1H), 7.35-7.17 (m, 1H), methyl-7-oxo-1H- 6.32-6.17 (m, 1H), 4.01-3.72 (m, 1H), 3.53 (s, pyrrolo[2,3-c]pyridine-4- 3H), 2.95-2.77 (m, 2H), 2.77-2.57 (m, carboxamide 2H), 2.22-2.06 (m, 2H), 2.06-1.89 (m, 2H), 1.89-1.69 (m, 2H), 0.95 (dd, J = 11.4, 6.6 Hz, 6H), 0.65-0.50 (m, 2H), 0.50-0.37 (m, 2H).

Example 244 6-methyl-4-(methylamino)piperidine-1-carbonyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

A mixture of 6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-carboxylic acid (Intermediate C) (60 mg, 0.3 mmol), triethylamine (90 mg, 0.9 mmol), HATU (200 mg, 0.5 mmol) and tert-butyl N-methyl-N-(4-piperidyl)carbamate (110 mg, 0.5 mmol) in DMF (1 mL) was stirred at 50° C. for 2 h. The reaction mixture was added to water (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure to yield tert-butyl N-methyl-N-[1-(6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carbonyl)-4-piperidyl]carbamate (100 mg). This intermediate was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (0.1 mL) was then added. The mixture was stirred for 1 h at room temperature at which time LCMS indicated that the reaction had gone to completion. The mixture was concentrated under reduced pressure and the residue was purified by SFC chromatography (10-20% CO2/0.1% NH4OH in MeOH) to give the title compound (54 mg, 60% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d6) δ 7.40 (s, 1H), 7.33 (d, J=2.8 Hz, 1H), 6.24 (d, J=2.8 Hz, 1H), 3.98 (s, 1H), 3.53 (s, 3H), 3.06-2.95 (m, 2H), 2.88 (m, J=15.9 Hz, 2H), 2.36 (s, 3H), 2.07 (s, 1H), 1.85 (d, J=12.8 Hz, 2H), 1.25 (d, J 11.3 Hz, 2H). LCMS M/Z (M+H) 289.2.

Example 245 6-(2-cyclopropylethyl)-4-(4-(dimethylamino)piperidine-1-carbonyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Step 1

methyl 6-(2-cyclopropylethyl)-7-oxo-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridin-1-carboxylate

Sodium hydride, 60% in mineral oil (35 mg, 0.87 mmol) was added to a cooled (0° C.) mixture of methyl 7-oxo-1-(p-tolylsulfonyl)-6H-pyrrolo[2,3-c]pyridine-4-carboxylate (Intermediate B, 200 mg, 0.58 mmol) in N,N-dimethylformamide (4 mL). The mixture was stirred for 15 min at 0° C. and then 2-bromoethylcyclopropane (100 mg, 0.69 mmol) was added. The reaction was allowed to warm to room temperature and stirring was continued for 18 h. The reaction was diluted with water (20 mL) and then extracted with ethyl acetate (3×10 mL). The combined organic extracts were washed with brine (2×20 mL), dried over sodium sulfate and concentrated under reduced pressure to yield the title compound (200 mg, 100% yield). This crude was used directly in the next step. LCMS M/Z (M+H) 415.4.

Step 2

6-(2-cyclopropylethyl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-carboxylic acid

A mixture of methyl 6-(2-cyclopropylethyl)-7-oxo-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridine-4-carboxylate (200 mg, 0.5 mmol) and lithium hydroxide (50 mg, 2 mmol) in dichloromethane (4 mL), methanol (6 mL) and water (1 mL) was stirred at 45° C. for 5 h. The mixture was concentrated under reduced pressure and the residue was dissolved in water (4 mL). The aqueous solution was acidified to pH 1 with 1N hydrochloric acid. The resulting precipitate was collected by filtration, washed with water, and dried to yield the title compound (100 mg, 80% yield) as a brown solid. LCMS M/Z (M+H) 247.2.

Step 3

6-(2-cyclopropylethyl)-4-(4-(dimethylamino)piperidine-1-carbonyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

A mixture of 6-(2-cyclopropylethyl)-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carboxylic acid (50 mg, 0.2 mmol), triethylamine (80 mg, 0.8 mmol), HATU (90 mg, 0.3 mmol) and N,N-dimethylpiperidin-4-amine (30 mg, 0.3 mmol) in N,N-dimethylformamide (1 mL) was stirred at 50° C. for 1 h. The reaction mixture was added to water (5 mL) and extracted with ethyl acetate (3×10 mL). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC (0-25%/ACN/0.1% NH4OH in H2O) to give 6-(2-cyclopropylethyl)-4-(4-(dimethylamino)piperidine-1-carbonyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one (22 mg, 30% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d6) δ 12.09 (s, 1H), 7.41 (s, 1H), 7.33 (d, J=2.8 Hz, 1H), 6.24 (d, J=2.8 Hz, 1H), 4.06 (t, J=7.1 Hz, 2H), 3.03-2.80 (m, 2H), 2.30 (dd, J=12.7, 8.9 Hz, 1H), 2.16 (s, 6H), 1.75 (d, J=12.3 Hz, 2H), 1.56 (q, J=7.0 Hz, 2H), 1.30 (d, J=11.9 Hz, 2H), 0.77-0.58 (m, 1H), 0.44-0.30 (m, 2H). LCMS M/Z (M+H) 357.5.

The following compound was prepared in a similar fashion to Example 245.

Examples 246-249

Example Compound Name NMR m/z 246 6-but-2-enyl-4-[4- ¹H NMR (400 MHz, DMSO-d6) δ 12.14 (s, 343.2 (dimethylamino)piperidine- 1H), 7.45-7.25 (m, 2H), 6.25 (t, J = 2.3 Hz, 1-carbonyl]-1H- 1H), 5.77-5.50 (m, 2H), 4.55 (d, J = 5.4 Hz, pyrrolo[2,3-c]pyridin-7- 2H), 2.91 (t, J = 12.5 Hz, 2H), 2.32 (d, J = 3.9 Hz, one 1H), 2.17 (s, 6H), 1.75 (dd, J = 13.1, 4.0 Hz, 2H), 1.69-1.62 (m, 3H), 1.30 (dd, J = 11.6, 3.9 Hz, 2H). 247 6-but-3-enyl-4-[4- ¹H NMR (400 MHz, DMSO-d6) δ 12.11 (s, 343.2 (dimethylamino)piperidine- 1H), 7.36 (s, 1H), 7.33 (d, J = 2.7 Hz, 1H), 1-carbonyl]-1H- 6.23 (d, J = 2.7 Hz, 1H), 5.93-5.73 (m, 1H), pyrrolo[2,3-c]pyridin-7- 5.07-4.93 (m, 2H), 4.07 (t, J = 7.0 Hz, 2H), one 3.02-2.83 (m, 3H), 2.44 (t, J = 6.9 Hz, 2H), 2.30 (m, 1H), 2.17 (s, 6H), 1.75 (d, J = 12.6 Hz, 2H), 1.42-1.22 (m, 2H). 248 6-butyl-N-[(1-methyl-4- 1H NMR (400 MHz, DMSO) δ 12.01 (s, 1H), 345 piperidyl)methyl]-7-oxo- 7.94 (t, J = 5.7 Hz, 1H), 7.78 (s, 1H), 7.31 (d, J = 2.7 Hz, 1H-pyrrolo[2,3- 1H), 6.70 (d, J = 2.7 Hz, 1H), c]pyridine-4-carboxamide 4.08-3.91 (m, 2H), 3.13 (t, J = 6.3 Hz, 2H), 2.74 (d, J = 11.5 Hz, 2H), 2.12 (d, J = 5.4 Hz, 3H), 1.89-1.74 (m, 2H), 1.74-1.59 (m, 4H), 1.59-1.41 (m, 1H), 1.41-1.27 (m, 2H), 1.27-1.11 (m, 2H), 0.98-0.84 (m, 3H).

Example 249 6-allyl-N-[(1S,5R)-3-(2-cyanopyrimidin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl]-N-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carboxamide

Step 1:

tert-butyl (1R,5S)-6-[(2,4-dinitrophenyl)sulfonylamino]-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a flask was added tert-butyl (1R,5S)-6-amino-3-azabicyclo[3.1.0]hexane-3-carboxylate (500 mg, 2.50 mmol) and dichloromethane (50 mL). The solution was cooled to 0° C. and 2,6-lutidine (2.9 mL, 25.0 mmol) and 2,4-dinitrobenzenesulfonyl chloride (0.67 g, 2.50 mmol) were then added. The reaction was stirred at 0° C. for 30 minutes, then allowed to warm to room temperature and stirred overnight. The reaction was diluted with water (100 mL). This mixture was acidified to pH 2.5 using 5% potassium hydrogen sulfate in water. The organic phase was separated, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to afford crude title compound. This material was used directly in the next step assuming theoretical yield. LCMS M/Z (M−H) 427.

Step 2:

tert-butyl(1R,5S)-6-[(2,4-dinitrophenyl)sulfonyl-methyl-amino]-3-azabicyclo[3.1.0]hexane-3-carboxylate

The crude tert-butyl (1R,5S)-6-[(2,4-dinitrophenyl)sulfonylamino]-3-azabicyclo[3.1.0]hexane-3-carboxylate (107 mg, 0.25 mmol) was dissolved in N,N-dimethylformamide (20 mL), and cooled to 0° C. Sodium hydride (60% in mineral oil, 15 mg, 0.38 mmol) was then added and the reaction was stirred at 0° C. for 10 minutes. Iodomethane (0.047 mL, 0.75 mmol) was added. The reaction was allowed to warm to room temperature, and stirred for an additional 4 h. The reaction was then diluted with dichloromethane (100 mL), and washed with water. The organic solution was concentrated under reduced pressure and the residue was purified by silica gel chromatography (0-5% methanol:dichloromethane) yielding title compound (715 mg, 65% for 2 steps). ¹H NMR (400 MHz, DMSO-d₆) δ 9.02 (d, J=2.3 Hz, 1H), 8.61 (dd, J=8.7, 2.3 Hz, 1H), 8.29 (d, J=8.7 Hz, 1H), 3.49 (d, J=11.0 Hz, 2H), 3.35-3.27 (m, 4H), 2.90 (s, 3H), 2.10-2.01 (m, 3H), 1.35 (s, 9H).

Step 3:

tert-butyl (1R,5S)-6-[(6-allyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carbonyl)-methyl-amino]-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a 40 mL vial was added tert-butyl (1R,5S)-6-[(2,4-dinitrophenyl)sulfonyl-methyl-amino]-3-azabicyclo[3.1.0]hexane-3-carboxylate (650 mg, 1.47 mmol), dichloromethane (10 mL), and propan-1-amine (0.36 mL, 4.41 mmol). The reaction was stirred at room temperature for 4 h at which point LCMS showed loss of starting material. The reaction was concentrated under reduced pressure. This crude was carried on without purification.

To a 20 mL vial was added 6-allyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carboxylic acid (Example 159, step 1, 200 mg, 0.92 mmol), N,N-dimethylformamide (4 mL), HATU (365 mg, 0.96 mmol), and triethylamine (0.51 mL, 3.66 mmol). The reaction was capped and shaken at room temperature for 15 minutes. tert-Butyl (1R,5S)-6-(methylamino)-3-azabicyclo[3.1.0]hexane-3-carboxylate (1.3 equiv., 1.19 mmol) was then added, and the reaction was shaken for 1 h. The reaction was then diluted water (100 mL) and extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (2-5% methanol:dichloromethane), yielding title compound (127 mg, 34%). LCMS M/Z (M+H) Minor: 413, Major: 357 (loss of t-butyl fragment).

Step 4:

6-allyl-N-[(1R,5S)-3-azabicyclo[3.1.0]hexan-6-yl]-N-methyl-7-ox-1H-pyrrolo[2,3-c]pyridine-4-carboxamide; 2,2,2-trifluoroacetic acid

To a 4 mL vial was added tert-butyl (1R,5S)-6-[(6-allyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carbonyl)-methyl-amino]-3-azabicyclo[3.1.0]hexane-3-carboxylate (87 mg, 0.21 mmol), dichloromethane (0.5 mL), and trifluoroacetic acid (0.08 mL, 1.04 mmol). The reaction was capped and shaken at room temperature for 1 h, then concentrated under reduced pressure. The residue was azeotroped with ethanol (3×) and dichloromethane (3×) to afford the desired product, which was taken directly to the next step. LCMS M/Z (M+H) 313.

Step 5:

6-allyl-N-[(1S,5R)-3-(2-cyanopyrimidin-4-yl-3-azabicyclo[3.1.0]hexan-6-yl]-N-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carboxamide

To a 4 mL vial was added 6-allyl-N-[(1 S,5R)-3-azabicyclo[3.1.0]hexan-6-yl]-N-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carboxamide; 2,2,2-trifluoroacetic acid (40 mg, 0.094 mmol), acetonitrile (0.25 mL), diisopropylethylamine (0.049 mL, 0.28 mmol), and 4-chloropyrimidine-2-carbonitrile (14 mg, 0.10 mmol). The reaction was capped and shaken at 75° C. for 1 h. The reaction was concentrated under reduced pressure and the residue was purified by preparative HPLC (0-25% ACN/0.1% NH4OH in H2O) yielding 6-allyl-N-[(1 S,5R)-3-(2-cyanopyrimidin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl]-N-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carboxamide (35 mg, 89%). ¹H NMR (400 MHz, DMSO-d6) δ 12.12 (s, 1H), 8.22 (d, J=6.4 Hz, 1H), 7.46 (s, 1H), 7.33 (t, J=2.7 Hz, 1H), 6.67 (d, J=6.4 Hz, 1H), 6.34-6.28 (m, 1H), 6.01 (ddt, J=16.2, 10.7, 5.5 Hz, 1H), 5.20-5.05 (m, 2H), 4.69-4.61 (m, 2H), 3.61-3.30 (m, 4H), 3.00 (s, 3H), 2.68 (s, 1H), 1.97-1.86 (m, 2H). LCMS M/Z (M+H) 416.

The following compounds were prepared in a similar fashion to Example 249:

Examples 250-251

Example Compound Name NMR m/z 250 6-allyl-N-methyl-7-oxo-N- 1H NMR (400 MHz, DMSO-d6) δ 12.10 (d, J = 3.8 Hz, 459 [(1S,5R)-3-[4- 1H), 8.63 (dd, J = 5.0, 2.7 Hz, 1H), (trifluoromethyl)pyrimidin- 7.45 (d, J = 2.6 Hz, 1H), 7.31 (q, J = 2.5 Hz, 2-yl]-3- 1H), 7.00 (dd, J = 4.9, 2.7 Hz, 1H), 6.30 (d, J = 3.4 Hz, azabicyclo[3.1.0]hexan-6- 1H), 6.08-5.85 (m, 1H), yl]-1H-pyrrolo[2,3- 5.24-4.95 (m, 2H), 4.64 (d, J = 10.9 Hz, 2H), c]pyridine-4-carboxamide 3.52 (d, J = 10.8 Hz, 2H), 3.44-3.32 (m, 2H), 3.01 (d, J = 2.8 Hz, 3H), 2.69 (d, J = 2.7 Hz, 1H), 1.86 (s, 2H). 251 6-allyl-N-methyl-7-oxo-N- ¹H NMR (400 MHz, DMSO-d₆) δ 12.11 (s, 391 (3-pyrimidin-4-yl-3- 2H), 8.42 (d, J = 1.1 Hz, 1H), 8.11 (d, J = 6.0 Hz, azabicyclo[3.1.0]hexan-6- 1H), 7.46 (s, 1H), 7.35-7.29 (m, 1H), yl)-1H-pyrrolo[2,3- 6.40-6.28 (m, 2H),, 6.08-5.85 (m, 1H), c]pyridine-4-carboxamide 5.18-5.03 (m, 2H), 4.64 (d, J = 5.6 Hz, 2H), 3.31 (s, 4H), 3.01 (s, 3H), 2.69-2.63 (m, 1H), 1.89 (s, 2H).

Example 252 N,6-dimethyl-7-oxo-N-(1-phenethyl-4-piperidyl)-1H-pyrrolo[2,3-c]pyridine-4-carboxamide

To a microwave vial was added N,6-dimethyl-7-oxo-N-(4-piperidyl)-1H-pyrrolo[2,3-c]pyridine-4-carboxamide hydrochloride (Example 210, Step 1, 45 mg, 0.14 mmol), acetonitrile (0.2 mL), diisopropylethylamine (0.071 mL, 0.42 mmol), water (0.10 mL), and 2-bromoethylbenzene (39 mg, 0.21 mmol). The reaction was sealed and stirred under microwave irradiation for 30 minutes at 150° C. The reaction was then concentrated under reduced pressure and the residue was purified by preparative HPLC (5-50% ACN/0.1% NH4OH in H2O) yielding N,6-dimethyl-7-oxo-N-(1-phenethyl-4-piperidyl)-1H-pyrrolo[2,3-c]pyridine-4-carboxamide (22 mg, 41%).

The following compound was prepared in a similar fashion to Example 252.

Examples 253-255

Example Compound Name NMR m/z 253 N-[1-[2-(2- ¹H NMR (400 MHz, DMSO-d₆) δ 12.14 (s, 1H), 411 fluorophenyl)ethyl]-4- 7.40-7.18 (m, 4H), 7.17-7.07 (m, 2H), piperidyl]-N,6- 6.22-6.16 (m, 1H), 3.74 (s, 1H), 3.52 (s, 3H), dimethyl-7-oxo-1H- 3.02-2.95 (m, 2H), 2.82 (s, 3H), 2.74 (t, J = 7.7 Hz, pyrrolo[2,3- 2H), 2.46 (d, J = 7.5 Hz, 2H), 1.97-1.92 (m, 2H), c]pyridine-4- 1.85-1.71 (m, 2H), 1.65-1.58 (m, 2H). carboxamide 254 N-[1-[2-(4- ¹H NMR (400 MHz, DMSO-d₆) δ 12.13 (s, 1H), 427 chlorophenyl)ethyl]-4- 7.39-7.20 (m, 6H), 6.19 (dd, J = 2.8, 1.6 Hz, piperidyl]-N,6- 1H), 3.99 (s, 1H), 3.52 (s, 3H), 3.01-2.93 (m, dimethyl-7-oxo-1H- 2H), 2.82 (s, 3H), 2.70 (t, J = 7.5 Hz, 2H), pyrrolo[2,3- 1.95-1.90 (m, 2H), 1.84-1.70 (m, 2H), 1.65-1.57 (m, c]pyridine-4- 2H). carboxamide 255 N,6-dimethyl-7-oxo- ¹H NMR (400 MHz, DMSO-d₆) δ 12.13 (s, 1H), 407 N-[1-(2- 7.39-7.12 (m, 7H), 6.18 (dd, J = 2.8, 1.3 Hz, phenylpropyl)-4- 1H), 3.96 (s, 1H), 3.52 (s, 3H), 2.96-2.86 (m, piperidyl]-1H- 3H), 2.81 (s, 3H), 2.39-2.32 (m, 2H), pyrrolo[2,3- 1.94-1.89 (m, 1H), 1.82-1.68 (m, 3H), 1.63-1.54 (m, 2H), c]pyridine-4- 1.17 (d, J = 6.8 Hz, 3H). carboxamide

Example 256 (R)-6-methyl-7-oxo-N-(1-phenylethyl)-6,7-dihydro-1Hpyrrolo[2,3-c]pyridine-4-carboxamide

A vial was charged with 4-bromo-6-methyl-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridin-7-one (Intermediate D, 45 mg, 0.118 mmol), palladium acetate (2.65 mg, 0.012 mmol), and Xantphos (6.83 mg, 0.012 mmol) before being evacuated and purged with carbon monoxide (3×). Toluene (2 mL) was added, followed by (R)-1-phenylethanamine (28.6 mg, 0.236 mmol), and triethylamine (82 μl, 0.590 mmol), and the reaction mixture was stirred at 90° C. for 2 h. After cooling, the mixture was diluted with ethyl acetate and filtered through a pad of Celite. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography (eluting with hexanes and ethyl acetate) to afford crude intermediate. This material was dissolved in methanol (6 mL) and then potassium hydroxide (33.1 mg, 0.590 mmol) in water (1 mL) was added. The reaction was stirred at room temperature 18 h. The reaction was filtered through Celite, using methanol to rinse and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with hexanes and ethyl acetate) to give the title compound as a white, amorphous solid (10 mg, 29%) after lyophilization from dioxane. ¹H NMR (400 MHz, DMSO-d6) δ 12.02-12.10 (m, 1H), 8.34 (d, J=7.69 Hz, 1H), 7.94 (s, 1H), 7.40 (d, J=7.06 Hz, 2H), 7.28-7.36 (m, 3H), 7.23 (d, J=7.27 Hz, 1H), 6.67 (t, J=2.29 Hz, 1H), 5.14 (s, 1H), 3.57 (s, 3H), 1.46 (d, J=7.27 Hz, 3H). LCMS M/Z (M+H) 296.

The following compounds were prepared in a similar fashion to Example 256:

Examples 257-264

Example Compound Name NMR m/z 257 N-benzyl-6-methyl-7- 1H NMR (400 MHz, DMSO-d6) δ 12.10 (br. s., 282 oxo-1H-pyrrolo[2,3- 1H), 8.52 (t, J = 6.02 Hz, 1H), 7.91 (s, 1H), c]pyridine-4- 7.34 (s, 1H), 7.30-7.34 (m, 2H), 7.20-7.28 (m, 1H), carboxamide 6.70-6.77 (m, 1H), 4.46 (d, J = 6.02 Hz, 1H), 3.55 (s, 3H). 258 6-methyl-7-oxo-N-(2- ¹H NMR (400 MHz, DMSO-d6) δ 12.08 (br. s., 296 phenylethyl)-1H- 1H), 8.03 (br. s., 1H), 7.79 (s, 1H), pyrrolo[2,3-c]pyridine- 7.18-7.34 (m, 4H), 6.66 (t, J = 2.39 Hz, 1H), 3.54 (s, 3H), 4-carboxamide 3.43-3.51 (m, 2H), 2.84 (t, J = 7.48 Hz, 2H). 259 N-benzyl-6-butyl-7-oxo- ¹H NMR (400 MHz, DMSO-d6) δ 324 1H-pyrrolo[2,3- 12.02-12.10 (m, 1H), 8.47-8.58 (m, 1H), 7.88 (s, 1H), c]pyridine-4- 7.31-7.37 (m, 4H), 7.21-7.28 (m, 1H), carboxamide 6.73-6.77 (m, 1H), 4.47 (d, J = 6.02 Hz, 2H), 3.93-4.04 (m, 2H), 1.62-1.75 (m, 2H), 1.25-1.39 (m, 2H), 0.87-0.96 (m, 3H). 260 N-benzyl-6-[(E)-but-2- ¹H NMR (400 MHz, DMSO-d6) δ 322 enyl]-7-oxo-1H- 11.98-12.21 (m, 2H), 8.46-8.58 (m, 1H), 7.82 (s, 1H), pyrrolo[2,3-c]pyridine- 7.31-7.38 (m, 5H), 7.20-7.28 (m, 1H), 4-carboxamide 6.72-6.77 (m, 1H), 5.63 (s, 2H), 4.64-4.72 (m, 1H), 4.52-4.59 (m, 2H), 4.47 (d, J = 5.82 Hz, 2H), 1.75-1.81 (m, 1H), 1.66 (d, J = 4.36 Hz, 3H). 261 N-[(4- ¹H NMR (400 MHz, DMSO-d6) δ 12.09 (br. s., 312 methoxyphenyl)methyl]- 1H), 8.42 (t, J = 6.02 Hz, 1H), 7.88 (s, 1H), 6-methyl-7-oxo-1H- 7.32 (t, J = 2.80 Hz, 1H), 7.26 (d, J = 8.72 Hz, 2H), pyrrolo[2,3-c]pyridine- 6.86-6.92 (m, 2H), 6.73 (t, J = 2.39 Hz, 1H), 4-carboxamide 4.38 (d, J = 5.82 Hz, 2H), 3.73 (s, 3H), 3.54 (s, 3H). 262 6-methyl-7-oxo-N-(2- ¹H NMR (400 MHz, DMSO-d6) δ 12.10 (br. s., 288 thienylmethyl)-1H- 1H), 8.59 (s, 1H), 7.87 (s, 1H), 7.39 (d, J = 4.99 Hz, pyrrolo[2,3-c]pyridine- 1H), 7.33 (t, J = 2.80 Hz, 1H), 7.02 (br. s., 4-carboxamide 1H), 6.94-7.00 (m, 1H), 6.74 (s, 1H), 4.61 (d, J = 5.82 Hz, 3H), 3.54 (s, 3H). 263 N-[(4- ¹H NMR (400 MHz, DMSO-d6) δ 12.10 (br. s., 300 fluorophenyl)methyl]-6- 1H), 8.52 (t, J = 5.92 Hz, 1H), 7.90 (s, 1H), methyl-7-oxo-1H- 7.34-7.42 (m, 2H), 7.33 (t, J = 2.80 Hz, 1H), pyrrolo[2,3-c]pyridine- 7.11-7.20 (m, 2H), 6.74 (t, J = 2.49 Hz, 1H), 4.44 (d, 4-carboxamide J = 5.82 Hz, 2H), 3.55 (s, 3H). 264 6-methyl-7-oxo-N- ¹H NMR (400 MHz, DMSO-d6) δ 12.06 (br. s., 296 [(1S)-1-phenylethyl]- 1H), 8.34 (d, J = 7.89 Hz, 1H), 7.94 (s, 1H), 1H-pyrrolo[2,3- 7.37-7.45 (m, 2H), 7.28-7.36 (m, 3H), 7.23 (d, J = 7.48 Hz, c]pyridine-4- 1H), 6.67 (s, 1H), 5.06-5.21 (m, 1H), carboxamide 3.57 (s, 3H), 1.47 (d, J = 7.06 Hz, 3H).

Example 265 6-methyl-7-oxo-N-(6,7,8,9-tetrahydro-5Hbenzo[7]annulen-5-yl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-carboxamide

Step 1:

6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-amine

A round bottomed flask was charged with 6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (1 ml, 6.68 mmol), isopropanol (70 mL), sodium cyanoborohydride (2.94 g, 46.8 mmol), and ammonium acetate (15.46 g, 201 mmol). The mixture was stirred at room temperature for 4 h and then heated to reflux overnight. After cooling, the reaction was quenched with 1 N sodium hydroxide (100 mL) and extracted with dichloromethane (3×50 mL). The combined organic extracts were washed with water, dried with sodium sulfate, and concentrated under reduced pressure to give a crude residue that contained 6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-amine. This material was used directly in the following amide bond formation.

Step 2:

6-methyl-7-oxo-N-(6,7,8,9-tetrahydro-5Hbenzo[7]annulen-5-yl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-carboxamide

The following example was prepared in a similar fashion to Example 256 using 6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-amine (synthesis step 1). ¹H NMR (400 MHz, DMSO-d6) δ 12.00-12.13 (m, 1H), 8.37-8.46 (m, 1H), 8.07 (s, 1H), 7.29-7.33 (m, 1H), 7.22-7.28 (m, 1H), 7.13 (d, J=4.57 Hz, 3H), 6.66-6.72 (m, 1H), 5.17-5.27 (m, 1H), 3.60 (s, 3H), 2.78-2.94 (m, 2H), 1.60-2.01 (m, 4H), 1.21-1.36 (m, 2H). LCMS M/Z (M+H) 336.

Example 266 6-methyl-7-oxo-N-(6,7,8,9-tetrahydro-5Hbenzo[7]annulen-5-yl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-carboxamide

The following example was prepared in a similar fashion to Example 159 using 6-allyl-2-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-carboxylic acid (Intermediate F). 1H NMR (400 MHz, DMSO-d6) δ 11.91 (s, 1H), 7.24 (s, 1H), 6.57 (s, 1H), 6.05-5.90 (m, 2H), 5.16 (dq, J=10.3, 1.5 Hz, 1H), 5.04 (dq, J=17.1, 1.6 Hz, 1H), 4.61 (dd, J=4.3, 2.7 Hz, 2H), 4.52 (d, J=13.2 Hz, 2H), 2.82-2.74 (m, 5H), 2.37-2.21 (m, 7H), 1.91-1.79 (m, 1H), 1.73-1.63 (m, 4H), 0.98-0.80 (m, 4H). LCMS M/Z (M+H) 461.

Example 267 6-allyl-N-(1-(2-cyclopropyl-6-methylpyrimidin-4-yl)piperidin-4-yl)-N,2-dimethyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-carboxamide

The following example was prepared in a similar fashion to Example 159 using 6-allyl-2-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-carboxylic acid (Intermediate F). 1H NMR (400 MHz, DMSO-d6) δ 11.90 (s, 1H), 7.24 (s, 1H), 6.48 (s, 1H), 6.05-5.90 (m, 2H), 5.16 (dq, J=10.3, 1.4 Hz, 1H), 5.04 (dq, J=17.0, 1.6 Hz, 1H), 4.61 (dt, J=5.8, 1.5 Hz, 2H), 4.48 (d, J=13.1 Hz, 2H), 4.31 (s, 0H), 2.92-2.71 (m, 5H), 2.32 (s, 3H), 2.18 (s, 3H), 1.89 (tt, J=7.9, 4.8 Hz, 1H), 1.73-1.61 (m, 4H), 0.93-0.77 (m, 4H). LCMS M/Z (M+H) 461.

Example 268 6-allyl-N,2-dimethyl-N-[1-[6-(2-methyl-3-pyridyl)pyrimidin-4-yl]-4-piperidyl]-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carboxamide

Step 1

tert-butyl (1-(6-chloropyrimidin-4-yl)piperidin-4-yl)(methyl)carbamate

To a solution of 4,6-dichloropyrimidine (5.2 g, 35.0 mmol) in DMF (100 mL) were added tert-butyl methyl(piperidin-4-yl)carbamate (5.0 g, 23.3 mmol) and cesium carbonate (15.2 g, 46.7 mmol). After addition, the reaction mixture was heated at 80° C. for 16 h, at which time LCMS indicated the reaction had gone to completion. The solution was poured into ice water, and extracted with ethyl acetate (3×20 mL). The combined organic layers were concentrated under reduced pressure. The crude product was purified by silica gel chromatography column (Hexanes/ethyl acetate=5:1) to give the title compound (7.0 g, 92% yield) as a colorless oil.

Step 2

1-(6-chloropyrimidin-4-yl)-N-methylpiperidin-4-amine hydrochloride

To a solution of tert-butyl (1-(6-chloropyrimidin-4-yl)piperidin-4-yl)(methyl) carbamate (7.0 g, 21.4 mmol) in ethyl acetate (25 mL) was added a solution of hydrogen chloride (2 N in ethyl acetate, 10 mL). After addition, the mixture was stirred at room temperature for 3 h, at which time LCMS indicated the reaction had gone to completion. The solution was concentrated under reduced pressure to give the crude title compound (4.5 g, 80% yield) as a yellow oil.

Step 3

6-allyl-N-(1-(6-chloropyrimidin-4-yl)piperidin-4-yl)-N,2-dimethyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-carboxamide

To a solution of 6-allyl-2-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-carboxylic acid (3.0 g, 12.92 mmol) (Intermediate F) in DMF (100 mL) was added 1-(6-chloropyrimidin-4-yl)-N-methylpiperidin-4-amine hydrochloride (4.4 g, 16.7 mmol), HATU (5.9 g, 15.5 mmol) and triethylamine (2.6 g, 25.8 mmol). The resulting mixture was stirred at ambient temperature for 16 h, at which time LCMS indicated the reaction had gone to completion. The solution was poured into water (20 mL) and then extracted with ethyl acetate (3×100 mL). The combined organic layers were concentrated under reduced pressure. The crude product was purified by silica gel chromatography column (Hexanes/ethyl acetate=1:2) to give the title compound (2.8 g, 49% yield) as a yellow oil.

Step 4

6-allyl-N,2-dimethyl-N-[1-[6-(2-methyl-3-pyridyl)pyrimidin-4-yl]-4-piperidyl]-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carboxamide

A mixture of 6-allyl-N-(1-(6-chloropyrimidin-4-yl)piperidin-4-yl)-N,2-dimethyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-carboxamide (100 mg, 0.23 mmol), (2-methylpyridin-3-yl)boronic acid (47 mg, 0.34 mmol), cesium carbonate (148 mg, 0.45 mmol) and Pd(dppf)Cl₂ (20 mg, 0.03 mmol) in dioxane/H₂O (5:1, 3 mL) was heated at 85° C. under microwave conditions for 0.5 h, at which time LCMS indicated the reaction had gone to completion. The solvent was evaporated under reduced pressure and the crude product was purified by reverse phase chromatography (acetonitrile 30-50%/0.1% NH₄OH in water) to give the title compound (24 mg, 21% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 11.95 (s, 1 H), 8.58 (s, 1 H), 8.51-8.50 (m, 1 H), 7.81-7.78 (m, 1 H), 7.34-7.31 (m, 1 H), 7.26 (s, 1 H), 7.03 (s, 1 H), 6.02-5.93 (m, 2 H), 5.17-5.14 (m, 1 H), 5.06-5.02 (m, 1 H), 4.62-4.61 (m, 4 H), 4.35-4.32 (s, 1H), 3.93-3.89 (m, 2 H), 2.90 (s, 3 H), 2.79 (s, 3 H), 2.32 (s, 3 H), 1.76-1.72 (m, 4 H). LCMS M/Z (M+H) 498.

The following compounds were prepared in a similar fashion to Example 268:

Examples 269-270

Example Compound Name NMR m/z 269 6-allyl-N-[1-[6-(2- ¹H NMR (400 MHz, DMSO-d₆): δ 8.47 (s, 1 473 furyl)pyrimidin-4-yl]-4- H), 7.88-7.87 (m, 1 H), 7.26 (s, 1 H), piperidyl]-N,2-dimethyl-7- 7.20-7.19 (m, 1 H), 7.06 (s, 1 H), 6.68-6.66 (m, 1 oxo-1H-pyrrolo[2,3- H), 6.03-5.93 (m, 1 H), 5.18-5.15 (m, 1 H), c]pyridine-4-carboxamide 5.07-5.02 (m, 1 H), 4.63-4.61 (m, 4 H), 4.37-4.35 (s, 1 H), 2.94-2.90 (m, 2 H), 2.78 (s, 3 H), 2.32 (s, 3 H), 1.76-1.72 (m, 4 H). 270 6-allyl-N-[1-[6-(2- ¹H NMR (400 MHz, DMSO-d₆): δ 11.94 (s, 1 517 chlorophenyl)pyrimidin-4- H), 8.58 (s, 1 H), 7.56-7.54 (m, 2 H), yl]-4-piperidyl]-N,2- 7.47-7.45 (m, 2 H), 7.26 (s, 1 H), 7.04 (s, 1 H), dimethyl-7-oxo-1H- 6.01-5.94 (m, 2 H), 5.17-5.14 (m, 1 H), pyrrolo[2,3-c]pyridine-4- 5.06-5.01 (m, 1 H), 4.62-4.61 (m, 4 H), carboxamide 4.36-4.33 (s, 1 H), 3.93-3.89 (m, 2 H), 2.78 (s, 3 H), 2.32 (s, 3 H), 1.76-1.72 (m, 4 H).

Example 271 6-allyl-N,2-dimethyl-7-oxo-N-[1-[6-(2-pyridyl)pyrimidin-4-yl]-4-piperidyl]-1H-pyrrolo[2,3-c]pyridine-4-carboxamide

Step 1

tert-butyl methyl(1-(6-(pyridin-2-yl)pyrimidin-4-yl)piperidin-4-yl)carbamate

A mixture of tert-butyl (1-(6-chloropyrimidin-4-yl)piperidin-4-yl)(methyl)carbamate (500 mg, 1.53 mmol), 2-(tributylstannyl)pyridine (845 mg, 2.30 mmol), Pd(OAc)₂ (200 mg, 0.89 mmol) and X-Phos (100 mg, 0.21 mmol) in dioxane (10 mL) was heated at 120° C. under microwave conditions for 30 min, at which time LCMS indicated the reaction had gone to completion. After cooled, the reaction mixture was quenched by addition of water (30 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were concentrated under reduced pressure. The crude product was purified by silica gel chromatography (Hexanes/ethyl acetate=3:1) to give the title compound (300 mg, 53% yield) as a colorless oil.

Step 2

N-methyl-1-(6-(pyridin-2-yl)pyrimidin-4-yl)piperidin-4-amine hydrochloride

To a solution of tert-butyl methyl(1-(6-(pyridin-2-yl)pyrimidin-4-yl)piperidin-4-yl) carbamate (300 mg, 0.81 mmol) in ethyl acetate (10 mL) was added hydrogen chloride (2 N in Ethyl acetate, 10 mL). After addition, the reaction mixture was stirred at ambient temperature for 2 h, at which time LCMS indicated the reaction had gone to completion. The solvent was evaporated under reduced pressure to give the title compound (200 mg, 81% yield) as a yellow solid.

Step 3:

6-allyl-N,2-dimethyl-7-oxo-N-[1-[6-(2-pyridyl)pyrimidin-4-yl]-4-piperidyl]-1H-pyrrolo[2,3-c]pyridine-4-carboxamide

To a solution of 6-allyl-2-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-carboxylic acid (100 mg, 0.43 mmol) in DMF (5 mL) was added N-methyl-1-(6-(pyridin-2-yl)pyrimidin-4-yl)piperidin-4-amine hydrochloride (158 mg, 0.52 mmol), HATU (213 mg, 0.56 mmol) and N-ethyl-N-isopropylpropan-2-amine (178 mg, 1.38 mmol). After addition, the reaction mixture was stirred at ambient temperature for 8 h, at which time LCMS indicated the reaction had gone to completion. The reaction mixture was diluted with H₂O (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were concentrated under reduced pressure. The crude product was purified by reverse phase chromatography (acetonitrile 45-75%/0.1% NH₄OH in water) to give title compound (26 mg, 12%) as a yellow solid. ¹H NMR (400 MHz, CD₃OD): δ 8.67 (d, J=4.4 Hz, 1H), 8.57 (s, 1H), 8.27 (d, J=8.0 Hz, 1 H), 8.01-7.90 (m, 1 H), 7.67 (s, 1 H), 7.51-7.43 (m, 1H), 7.31 (s, 1 H), 6.10-5.97 (m, 2 H), 5.22 (d, J=10.4 Hz, 1 H), 5.14 (d, J=17.2 Hz, 1 H), 4.85-4.62 (m, 5H), 3.25-3.01 (m, 2 H), 2.91 (s, 3 H), 2.43 (s, 3 H), 1.95-1.82 (m, 4 H). LCMS M/Z (M+H) 484.

The following compound was prepared in a similar fashion to Example 271:

Example Compound Name NMR m/z 272 6-allyl-N,2-dimethyl- ¹H NMR (400 MHz, DMSO-d₆): δ 11.94 (s, 1 H), 498 N-[1-[6-(3-methyl-2- 8.58 (s, 1 H), 8.50-8.49 (m, 1 H), 7.74-7.72 (m, 1 pyridyl)pyrimidin-4- H), 7.40-7.37 (m, 1 H), 7.27 (s, 1 H), 7.17 (s, 1 yl]-4-piperidyl]-7- H), 6.01-5.94 (m, 2 H), 5.18-5.15 (m, 1 H), oxo-1H-pyrrolo[2,3- 5.07-5.02 (m, 1H), 4.63-4.61 (m, 4 H), 4.38-4.34 (s, 1 c]pyridine-4- H), 3.93-3.89 (m, 2 H), 2.79 (s, 3 H), 2.45 (s, 3 carboxamide H), 2.32 (s, 3 H), 2.32 (s, 3 H), 1.76-1.72 (m, 4 H).

Example 273 and Example 274 1-(6-allyl-2-methyl-7-oxo-,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-carbonyl)-4-(4-fluorophenyl)piperazine-2-carboxamide

Step 1

1-tert-butyl 2-methyl 4-(4-fluorophenyl)piperazine-1,2-dicarboxylate

In 9 parallel batches, A mixture of tert-butyl 2-methyl piperazine-1,2-dicarboxylate (1.0 g, 4.09 mmol), (4-fluorophenyl)boronic acid (1.72 g, 12.28 mmol), Copper(II) acetate (1.5 g, 8.19 mmol), pyridine (647 mg, 8.19 mmol) and sodium bicarbonate (688 mg, 8.19 mmol) in dichloromethane (50 ml) was stirred at ambient temperature under 02 (balloon) for 60 h, at which time LCMS indicated the reaction had gone to completion. The combined solutions were concentrated under reduced pressure. The residue was dissolved in ethyl acetate (50 mL), washed with water (2×40 mL) and concentrated. The crude product was purified by silica gel chromatography column (Hexanes/ethyl acetate=5:1) to give the title compound (9.8 g, yield 79%) as a brown oil. ¹H NMR (400 MHz, CDCl₃): δ 6.91-6.80 (m, 2 H), 6.80-6.62 (m, 2 H), 4.86-4.68 (m, 1 H), 4.05-3.88 (m, 2 H), 3.77 (s, 3 H), 3.37-3.15 (m, 2 H), 2.90-2.86 (m, 1 H), 2.77-2.68 (m, 1 H), 1.49-1.40 (m, 9 H). LCMS M/Z (M+H) 338.

Step 2

1-(tert-butoxycarbonyl)-4-(4-fluorophenyl)piperazine-2-carboxylic acid

To a solution of 1-tert-butyl 2-methyl 4-(4-fluorophenyl) piperazine-1,2-dicarboxylate (5.8 g, 17.14 mmol) in MeOH (80 mL) was added a solution of lithium hydroxide (1.64 g, 68.56 mmol) in water (10 mL). After addition, the reaction mixture was stirred at 30° C. for 2 h, at which time LCMS indicated the reaction had gone to completion. The solvent was evaporated under reduced pressure. The residue was diluted with water (20 mL), adjusted to pH=4-5 with 1 N aqueous hydrochloric acid and then extracted with ethyl acetate (2×30 mL). The combined organic layers were concentrated to give the crude title compound (5.6 g, 99% yield) as a brown oil.

Step 3

tert-butyl 2-carbamoyl-4-(4-fluorophenyl)piperazine-1-carboxylate

To a solution of 1-(tert-butoxycarbonyl)-4-(4-fluorophenyl) piperazine-2-carboxylic acid (5.6 g, 17.3 mmol) in DMF (100 mL) was added N-ethyl-N-isopropylpropan-2-amine (12.3 mL, 69.1 mmol), HATU (9.8 g, 25.9 mmol) and NH₄Cl (2.77 g, 51.8 mmol). The reaction mixture was stirred at ambient temperature for 18 h, at which time LCMS indicated the reaction had gone to completion. The solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (200 mL), washed with water (2×70 mL) and concentrated. The crude product was purified by silica gel chromatography (Hexanes/ethyl acetate=1:1) to give the title compound (4.8 g, 86% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃): δ 6.96-6.86 (m, 4 H), 6.04 (br., s, 2 H), 4.85-4.65 (m, 1 H), 4.20-4.08 (m, 2 H), 3.37-3.14 (m, 2 H), 2.83-2.65 (m, 2 H), 1.49 (s, 9 H).

Step 4

4-(4-fluorophenyl)piperazine-2-carboxamide hydrochloride

To a solution of tert-butyl 2-carbamoyl-4-(4-fluorophenyl)piperazine-1-carboxylate (980 mg, 3.03 mmol) in methanol (10 mL) was added hydrogen chloride (2 N in ethyl acetate, 10 mL). The resulting mixture was stirred at ambient temperature for 2 h, at which time LCMS indicated the reaction had gone to completion. The solvent was evaporated under reduced pressure to give the crude title compound (700 mg, 89% yield) as a white solid.

Step 5

1-(6-allyl-2-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-carbonyl)-4-(4-fluorophenyl)piperazine-2-carboxamide (fraction 1) and 1-(6-allyl-2-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-carbonyl)-4-(4-fluorophenyl)piperazine-2-carboxamide (fraction 2)

To a solution of 6-allyl-2-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-carboxylic acid (Intermediate F) (2.5 g, 12.14 mmol) in DMF (50 mL) was added 4-(4-fluorophenyl)piperazine-2-carboxamide (4.0 g, 15.78 mmol), HATU (4.8 g, 12.75 mmol) and N-ethyl-N-isopropylpropan-2-amine (6.3 g, 48.56 mmol). The resulting mixture was heated at 60° C. for 18 h, at which time LCMS indicated the reaction had gone to completion. The mixture was quenched by addition of water (80 mL) and the precipitate was collected by filtration. The solid was washed with water and dried in vacuum to give the mixture of enantiomers (3.1 g, 59% yield) as a brown solid. The enantiomers were separated by using chiral SFC (SFC80; Chiralpak AD 300×50 mm I.D., 5 um; Supercritical CO₂/EtOH+NH₃:H₂O=55/45; 200 ml/min) to give the title compounds as white solids.

Fraction 1 (976 mg, 18% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 11.98 (s, 1 H), 7.54 (s, 1 H), 7.41-7.16 (m, 2 H), 7.14-7.00 (m, 2 H), 6.97-6.85 (m, 2 H), 6.18 (br. s, 1 H), 6.00-5.92 (m, 1 H), 5.16 (d, J=10.4, 1 H), 5.05 (d, J=17.2, 1 H), 4.61 (s, 2 H), 4.12-4.03 (m, 1 H), 3.75-3.37 (m, 4 H), 2.89 (d, J=9.6, 1 H), 2.70-2.58 (m, 1 H), 2.32 (s, 3 H). LCMS M/Z (M+H) 438. SFC retention time: 0.63 min.

Fraction 2 (833 mg, 16% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 11.97 (s, 1 H), 7.53 (s, 1 H), 7.40-7.15 (m, 2 H), 7.13-7.01 (m, 2 H), 6.95-6.86 (m, 2 H), 6.17 (br. s, 1 H), 5.99-5.92 (m, 1 H), 5.15 (d, J=10.0, 1 H), 5.05 (d, J=16.8, 1 H), 4.61 (s, 2 H), 4.10-4.01 (m, 1 H), 3.70-3.37 (m, 4 H), 2.89 (d, J=9.6, 1 H), 2.69-2.58 (m, 1 H), 2.31 (s, 3 H). LCMS M/Z (M+H) 438. SFC retention time: 2.15 min.

Example 275 6-allyl-N,2-dimethyl-7-oxo-N-tetralin-1-yl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide

Title compound was prepared in a similar fashion as Example 244 using Intermediate F. ¹H NMR (400 MHz, DMSO-d₆) δ 11.93 (s, 1H), 7.36 (s, 1H), 7.24-7.08 (m, 4H), 6.06 (s, 1H), 6.03-5.93 (m, 1H), 5.22-4.94 (m, 3H), 4.77-4.48 (m, 2H), 2.62 (s, 5H), 2.33 (s, 3H), 2.14-1.80 (m, 4H). LCMS M/Z (M+H) 376.

Example 276 6-allyl-N,2-dimethyl-7-oxo-N-tetralin-1-yl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide

Step 1:

tert-butyl N-(5,6,7,8-tetrahydroquinolin-5-yl)carbamate

To a 20 mL vial was added 5,6,7,8-tetrahydroquinolin-5-amine (500 mg, 3.4 mmol) followed by tert-butoxycarbonyl tert-butyl carbonate (773 mg, 3.5 mmol), 6 mL of tetrahydrofuran, and 6 mL of saturated sodium bicarbonate. The reaction was shaken at room temperature for 1 h. LCMS showed product formation. The reaction was diluted with ethyl acetate, and washed with water. Organic phase was then concentrated under reduced pressure. The crude product was carried on directly without purification. LCMS M/Z (M+H) 249.

Step 2:

N-methyl-5,6,7,8-tetrahydroquinolin-5-amine dihydrochloride

Tert-butyl N-(5,6,7,8-tetrahydroquinolin-5-yl)carbamate (110 mg, 0.44 mmol) was taken up with 3 mL of N,N-dimethylformamide, and sodium hydride 60% in mineral oil (53 mg, 1.33 mmol) was then added. The reaction was stirred for 15 minutes, then iodomethane (0.028 mL, 0.44 mmol) was added. The reaction was capped and shaken at room temperature for 30 min. LCMS showed single addition.

The reaction was diluted with ethyl acetate, and quenched with water. The phases were separated, and the aqueous further extracted with ethyl acetate. The combined organics were concentrated under reduced pressure. LCMS M/Z (M+H) 263.

The crude product was then taken up with 5 mL of methanol followed by 5 mL of 4N HCl/dioxane. The reaction was stirred at room temperature for 1 h then concentrated under reduced pressure. The crude was carried on to the next reaction without purification.

Step 3:

6-allyl-N,2-dimethyl-7-oxo-N-tetralin-1-yl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide

Title compound was prepared in a similar fashion to Example 244, using Intermediate F. 1H NMR (400 MHz, DMSO-d6) δ 11.94 (s, 1H), 8.37 (d, J=4.9 Hz, 1H), 7.52-7.46 (m, 1H), 7.39 (s, 1H), 7.24 (dd, J=7.8, 4.7 Hz, 1H), 6.07 (s, 1H), 5.97 (ddd, J=15.8, 10.5, 5.2 Hz, 1H), 5.14 (d, J=10.3 Hz, 1H), 5.03 (d, J=17.3 Hz, 1H), 4.63 (s, 2H), 2.89 (d, J=0.5 Hz, 2H), 2.64 (s, 3H), 2.33 (s, 3H), 2.16-1.88 (m, 314). LCMS M/Z (M+H) 377.

The following compounds were prepared in a similar fashion to Example 276:

Examples 277-282

Example Compound Name NMR m/z 277 6-allyl-N-chroman-4- 1H NMR (400 MHz, DMSO-d6) δ 11.94 (s, 1H), 378 yl-N,2-dimethyl-7- 7.39 (s, 1H), 7.20-7.10 (m, 1H), 7.09-7.02 (m, oxo-1H-pyrrolo[2,3- 1H), 6.93 (td, J = 7.5, 1.2 Hz, 1H), 6.79 (d, J = 8.0 Hz, c]pyridine-4- 1H), 6.07 (s, 1H), 5.98 (ddt, J = 16.1, 10.5, 5.4 Hz, carboxamide 1H), 5.14 (d, J = 10.1 Hz, 1H), 5.10-5.00 (m, 1H), 4.63 (s, 2H), 4.31 (s, 1H), 4.15 (s, 1H), 2.64 (s, 3H), 2.33 (d, J = 0.8 Hz, 3H), 2.31-2.18 (m, 1H), 2.17-2.03 (m, 1H). 278 6-allyl-N-(7- 1H NMR (400 MHz, DMSO-d6) δ 11.95 (s, 1H), 396 fluorochroman-4-yl)- 7.44 (s, 1H), 7.06-6.96 (m, 1H), 6.87-6.78 (m, N,2-dimethyl-7-oxo- 2H), 6.12-6.02 (m, 1H), 5.97 (ddd, J = 17.2, 10.4, 1H-pyrrolo[2,3- 5.3 Hz, 1H), 5.14 (dd, J = 10.0, 1.7 Hz, 1H), c]pyridine-4- 5.05 (dd, J = 17.1, 1.8 Hz, 1H), 4.63 (d, J = 5.4 Hz, 2H), carboxamide 4.32 (d, J = 11.1 Hz, 1H), 4.14 (s, 1H), 2.67 (s, 3H), 2.34 (d, J = 0.9 Hz, 3H), 2.30-2.15 (m, 1H), 2.14-2.05 (m, 1H). 279 6-allyl-N-(4,4- 1H NMR (400 MHz, DMSO-d6) δ 11.93 (s, 1H), 404 dimethyltetralin-1- 7.39 (s, 2H), 7.19 (q, J = 6.8 Hz, 2H), 7.05 (s, 1H), yl)-N,2-dimethyl-7- 6.02 (d, J = 39.7 Hz, 2H), 5.09 (d, J = 40.2 Hz, oxo-1H-pyrrolo[2,3- 2H), 4.66 (s, 2H), 2.63 (s, 3H), 2.39-2.28 (m, c]pyridine-4- 3H), 2.06 (d, J = 5.2 Hz, 1H), 1.91 (dp, J = 13.1, carboxamide 5.1, 4.5 Hz, 1H), 1.74 (s, 2H), 1.25 (s, 6H). Enantiomer 1 280 6-allyl-N-(4,4- 1H NMR (400 MHz, DMSO-d6) δ 11.93 (s, 1H), 404 dimethyltetralin-1- 7.39 (s, 2H), 7.19 (q, J = 6.8 Hz, 2H), 7.05 (s, 1H), yl)-N,2-dimethyl-7- 6.02 (d, J = 39.7 Hz, 2H), 5.09 (d, J = 40.2 Hz, oxo-1H-pyrrolo[2,3- 2H), 4.66 (s, 2H), 2.63 (s, 3H), 2.39-2.28 (m, c]pyridine-4- 3H), 2.06 (d, J = 5.2 Hz, 1H), 1.91 (dp, J = 13.1, carboxamide 5.1, 4.5 Hz, 1H), 1.74 (s, 2H), 1.25 (s, 6H). Enantiomer 2 281 6-allyl-N-(6- ¹H NMR (400 MHz, DMSO-d₆) δ 11.94 (s, 1H), 406 methoxytetralin-1- 7.44-7.20 (m, 1H), 7.12-6.91 (m, 1H), yl)-N,2-dimethyl-7- 6.84-6.72 (m, 1H), 6.72-6.57 (m, 1H), 6.14-5.88 (m, oxo-1H-pyrrolo[2,3- 2H), 5.86-5.60 (m, 1H), 5.24-4.83 (m, 3H), c]pyridine-4- 4.80-4.47 (m, 2H), 3.72 (s, 3H), 2.87-2.57 (m, carboxamide, 5H), 2.33 (s, 3H), 2.19-1.75 (m, 4H). Enantiomer 1 282 6-allyl-N-(6- ¹H NMR (400 MHz, DMSO-d₆) δ 11.94 (s, 1H), 406 methoxytetralin-1- 7.44-7.20 (m, 1H), 7.12-6.91 (m, 1H), yl)-N,2-dimethyl-7- 6.84-6.72 (m, 1H), 6.72-6.57 (m, 1H), 6.14-5.88 (m, oxo-1H-pyrrolo[2,3- 2H), 5.86-5.60 (m, 1H), 5.24-4.83 (m, 3H), c]pyridine-4- 4.80-4.47 (m, 2H), 3.72 (s, 3H), 2.87-2.57 (m, carboxamide, 5H), 2.33 (s, 3H), 2.19-1.75 (m, 4H). Enantiomer 2

Example 283 6-allyl-N,2-dimethyl-7-oxo-N-(5,6,7,8-tetrahydroisoquinolin-5-yl)-1H-pyrrolo[2,3-c]pyridine-4-carboxamide

Step 1:

N-methyl-5,6,7,8-tetrahydroisoquinolin-5-amine

To a 20 mL vial was added 7,8-dihydro-6H-isoquinolin-5-one (200 mg, 1.36 mmol) followed by methanamine hydrochloride (275 mg, 4.08 mmol,), diisopropylethylamine (527 mg, 4.08 mmol), and 4 mL of 1,2-dichloroethane. The reaction was capped and shaken at 50° C. for 1 h. Sodium cyanoborohydride (261 mg, 4.08 mmol) was then added, and the reaction was capped and shaken at 50° C. for 72 h. LCMS shows desired product. The reaction was then diluted with DCM, and washed with 1N NaOH. The organic phase was concentrated under reduced pressure yielding crude product, which was carried on without purification. LCMS M/Z (M+H) 162.

Step 2:

6-allyl-N,2-dimethyl-7-oxo-N-(5,6,7,8-tetrahydroisoquinolin-5-yl)-1H-pyrrolo[2,3-c]pyridine-4-carboxamide

Title compound was prepared in a similar fashion to Example 244, using Intermediate F. ¹H NMR (400 MHz, DMSO-d₆) δ 11.94 (s, 1H), 8.36 (d, J=5.2 Hz, 2H), 7.40 (s, 1H), 7.08 (d, J=4.9 Hz, 1H), 6.08 (s, 1H), 5.97 (s, 1H), 5.21-4.98 (m, 2H), 4.63 (s, 2H), 2.74 (s, 2H), 2.66 (s, 3H), 2.34 (s, 3H), 2.16-1.75 (m, 4H). LCMS M/Z (M+H) 377.

The following compounds were prepared in a similar fashion to Example 283:

Examples 284-291

Example Compound Name NMR m/z 284 6-allyl-N-(7- ¹H NMR (400 MHz, DMSO-d₆) δ 11.96 (s, 394 fluorotetralin-1-yl)-N,2- 1H), 7.42 (s, 1H), 7.27-7.12 (m, 1H), dimethyl-7-oxo-1H- 7.08-6.96 (m, 1H), 6.90-6.72 (m, 1H), pyrrolo[2,3-c]pyridine-4- 6.12-5.90 (m, 2H), 5.83-5.55 (m, 1H), 5.22-4.97 (m, carboxamide 2H), 4.64 (s, 2H), 2.81-2.59 (m, 5H), 2.33 (s, 3H), 2.23-1.81 (m, 4H). 285 6-allyl-N,2-dimethyl-N- ¹H NMR (400 MHz, DMSO-d₆) δ 11.96 (s, 390 (5-methyltetralin-1-yl)-7- 1H), 7.32 (d, J = 32.2 Hz, 1H), 7.13-6.81 (m, oxo-1H-pyrrolo[2,3- 3H), 6.01 (d, J = 38.2 Hz, 2H), 5.77 (s, 1H), c]pyridine-4- 5.07 (d, J = 43.4 Hz, 3H), 4.65 (s, 2H), 2.65 (d, carboxamide J = 19.5 Hz, 5H), 2.33 (s, 3H), 2.26 (s, 4H), 2.10-1.81 (m, 4H). 286 6-allyl-N-(5- ¹H NMR (400 MHz, DMSO-d₆) δ 11.95 (s, 394 fluorotetralin-1-yl)-N,2- 1H), 7.38 (s, 1H), 7.32-7.17 (m, 1H), dimethyl-7-oxo-1H- 7.12-6.86 (m, 2H), 6.15-5.86 (m, 2H), 5.77 (s, pyrrolo[2,3-c]pyridine-4- 1H), 5.24-4.92 (m, 2H), 4.65 (s, 2H), carboxamide Enantiomer 1 2.86-2.56 (m, 5H), 2.33 (s, 3H), 2.16-1.73 (m, 4H). 287 6-allyl-N,2-dimethyl-N- 1H NMR (400 MHz, DMSO-d6) δ 390 (7-methyltetralin-1-yl)-7- 12.00-11.86 (m, 1H), 7.35 (s, 1H), 7.07 (dd, J = 22.6, oxo-1H-pyrrolo[2,3- 7.4 Hz, 2H), 6.94 (s, 1H), 6.01 (d, J = 35.4 Hz, c]pyridine-4- 2H), 5.79 (s, 1H), 5.23-4.88 (m, 2H), 4.65 (s, carboxamide Enantiomer 2 2H), 2.60 (s, 4H), 2.33 (s, 3H), 2.18 (s, 3H), 2.10-1.78 (m, 4H). 288 6-allyl-N-(5- ¹H NMR (400 MHz, DMSO-d₆) δ 11.94 (s, 406 methoxytetralin-1-yl)- 1H), 7.36 (s, 1H), 7.25-7.12 (m, 1H), N,2-dimethyl-7-oxo-1H- 6.89-6.76 (m, 1H), 6.76-6.64 (m, 1H), pyrrolo[2,3-c]pyridine-4- 6.13-5.88 (m, 2H), 5.88-5.69 (m, 1H), 5.25-4.87 (m, carboxamide Enantiomer 1 3H), 4.78-4.48 (m, 2H), 3.85-3.63 (m, 3H), 2.83-2.56 (m, 5H), 2.33 (s, 3H), 2.06-1.73 (m, 4H). 289 6-allyl-N-(5- ¹H NMR (400 MHz, DMSO-d₆) δ 11.94 (s, 406 methoxytetralin-1-yl)- 1H), 7.36 (s, 1H), 7.25-7.12 (m, 1H), N,2-dimethyl-7-oxo-1H- 6.89-6.76 (m, 1H), 6.76-6.64 (m, 1H), pyrrolo[2,3-c]pyridine-4- 6.13-5.88 (m, 2H), 5.88-5.69 (m, 1H), 5.25-4.87 (m, carboxamide Enantiomer 2 3H), 4.78-4.48 (m, 2H), 3.85-3.63 (m, 3H), 2.83-2.56 (m, 5H), 2.33 (s, 3H), 2.06-1.73 (m, 4H). 290 6-allyl-N,2-dimethyl-7- 1H NMR (400 MHz, DMSO-d6) δ 11.96 (s, 377 oxo-N-(5,6,7,8- 1H), 8.48-8.20 (m, 2H), 7.43 (s, 1H), 7.14 (d, tetrahydroisoquinolin-8- J = 4.8 Hz, 1H), 6.20-5.86 (m, 2H), 5.76 (s, yl)-1H-pyrrolo[2,3- 1H), 5.09 (dd, J = 39.2, 13.5 Hz, 2H), 4.65 (s, c]pyridine-4- 2H), 2.67 (s, 5H), 2.34 (s, 3H), 2.24-1.78 (m, carboxamide Enantiomer 1 4H). 291 6-allyl-N,2-dimethyl-7- 1H NMR (400 MHz, DMSO-d6) δ 11.96 (s, 377 oxo-N-(5,6,7,8- 1H), 8.48-8.20 (m, 2H), 7.43 (s, 1H), 7.14 (d, tetrahydroisoquinolin-8- J = 4.8 Hz, 1H), 6.20-5.86 (m, 2H), 5.76 (s, yl)-1H-pyrrolo[2,3- 1H), 5.09 (dd, J = 39.2, 13.5 Hz, 2H), 4.65 (s, c]pyridine-4- 2H), 2.67 (s, 5H), 2.34 (s, 3H), 2.24-1.78 (m, carboxamide Enantiomer 2 4H).

Example 292

Synthesis of biotinylated probe compound (1000) for TAF assay described below.

Step 1:

2-methoxy-4-methyl-3-nitropyridine

A solution of 2-chloro-4-methyl-3-nitropyridine (250 g, 1.45 mol) in methanol (1.0 L) was added dropwise (2 h) to a stirred and cooled (0° C.) solution of sodium methoxide (250 g, 4.63 mol) in methanol (850 mL). After addition, the mixture was heated to reflux for 23 h, at which time TLC indicated the reaction had gone to completion. The mixture was concentrated under reduced pressure to a volume of approximately 900 mL, and quenched by addition of water (1.5 L). The resulting solid was collected by filtration, washed with water and dried under reduced pressure to give the title compound (250 g, 100% yield) as a brown solid. ¹H NMR (400 MHz, DMSO-d6): δ 8.22 (d, J=5.2 Hz, 1 H), 7.10 (d, J=5.6 Hz, 1 H), 3.92 (s, 3 H), 2.26 (s, 3 H).

Step 2:

5-bromo-2-methoxy-4-methyl-3-nitropyridine

Sodium acetate (365 g, 5.37 mol) was added to a stirred solution of 2-methoxy-4-methyl-3-nitropyridine (250 g, 1.49 mol) in acetic acid (1.5 L) at ambient temperature and then Br₂ (639 g, 4.00 mol) was added dropwise (30 min). After addition, the mixture was heated at 80° C. for 12 h, at which time TLC indicated the reaction had gone to completion. The mixture was cooled (0° C.) and quenched by sequential addition of 10% aqueous (1.5 L) and saturated aqueous Na₂SO₃ (1.5 L). The resulting solid was collected by filtration washed with water, and dried under reduced pressure to give the title compound (302 g, 82.2% yield) as a light yellow solid. ¹H NMR (400 MHz, DMSO-d6): δ 8.25 (s, 1 H), 3.94 (s, 3 H), 2.29 (s, 3 H).

Step 3:

(E)-2-(5-bromo-2-methoxy-3-nitro-4-pyridyl)-N,N-dimethyl-ethenamine

DMF-DMA (600 mL) was slowly added to a stirred and heated (80° C.) solution of 5-bromo-2-methoxy-4-methyl-3-nitropyridine (134 g, 0.54 mol) in DMF (1.1 L). After addition, the mixture was heated at 95° C. for 5 h, at which time TLC indicated the reaction had gone to completion. The mixture was cooled to room temperature and poured into ice-cold water (3 L). The resulting red solid was collected by filtration, washed with water, and dried under reduced pressure to give the title compound (167 g, 100% yield) as red solid. ¹H NMR (400 MHz, DMSO-d6): δ 8.24 (s, 1 H), 7.05 (d, J=13.6 Hz, 1 H), 7.05 (d, J=13.6 Hz, 1 H), 4.80 (d, J=13.2 Hz, 1 H), 3.88 (s, 3 H), 2.90 (s, 6 H).

Step 4:

4-bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine

A mixture of 2-(5-bromo-2-methoxy-3-nitropyridin-4-yl)-N,N-dimethylethenamine (50.0 g, 165 mmol), Fe (50.0 g, 893 mmol) and NH₄Cl (50.0 g, 943 mmol) in methanol/H₂O (1900/250 mL) was heated at reflux for 7 h, at which time LCMS indicated that the reaction had gone to completion. The mixture was filtered while hot and the cake was washed with methanol (3×200 mL). The combined filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (petroleum ether: Ethyl acetate=5:1) to give the crude product. This crude material was triturated with acetonitrile to give the title compound (37.4 g, 99.5% yield) as a light brown solid. LCMS M/Z (M+H) 226.7, 228.7.

Step 5:

4-bromo-7-methoxy-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridine

A solution of 4-bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine (34.3 g, 0.15 mol) in THF (700 mL) was added dropwise to a stirred and cooled (0° C.) solution of sodium hydride (60%, 19.2 g, 0.48 mol) in THF (700 mL). After addition, the mixture was stirred at room temperature for 1 h, and then cooled again to 0° C. Tosyl chloride (38.0 g, 0.20 mol) in THF (700 mL) was added dropwise and the resulting mixture was stirred at ambient temperature for 2 h. The reaction was quenched by addition of saturated aqueous ammonium chloride (1.0 L), and then extracted with ethyl acetate (3×600 mL). The combined organic extracts were dried over Na₂SO₄ and concentrated under reduced pressure. The residue was triturated with acetonitrile to give the title compound (51.2 g, 88.9% yield) as a brown solid. This crude material was used in the next step without further purification.

Step 6:

4-bromo-1-(p-tolylsulfonyl)-6H-pyrrolo[2,3-c]pyridin-7-one

HBr (40% aqueous, 1.1 L) was added to a solution of 4-bromo-7-methoxy-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridine (102.5 g, 0.27 mol) in ethanol (200 mL). After addition, the mixture was heated at 90° C. for 2 h, at which time TLC indicated that the reaction had gone to completion. The mixture was cooled to 0° C. and the resulting white solid was collected by filtration. This solid was washed with water and dried under vacuum to give the title compound (87.5 g, 88.6% yield) as a light brown solid. ¹H NMR (400 MHz, DMSO-d6): δ 11.48 (s, 1 H), 8.01 (d, J=3.6 Hz, 1 H), 8.90 (d, J=8.0 Hz, 2 H), 7.38 (d, J=8.0 Hz, 2 H), 7.32 (s, 1 H), 6.57 (d, J=3.2 Hz, 1 H), 2.34 (s, 3 H).

Step 7:

4-bromo-6-methyl-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridin-7-one

Methyl iodide (24.5 g, 172.8 mmol) was added dropwise to a stirred suspension of 4-bromo-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one (Intermediate A) (16.7 g, 45.5 mmol) and cesium carbonate (17.8 g, 54.6 mmol) in dioxane (250 mL). After addition, the reaction mixture was stirred at room temperature for 18 h, at which time LCMS indicated the reaction had gone to completion. The solvent was evaporated under reduced pressure, and the residue was diluted with water (200 mL). The mixture was extracted with EtOAc (3×200 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate=3:1) to give the title compound (14.0 g, 81.4% yield) as a brown solid. ¹H NMR (400 MHz, DMSO-d6): δ 8.03 (d, J=3.6 Hz, 1 H), 7.92 (d, J=8.4 Hz, 2 H), 7.78 (s, 1 H), 7.39 (d, J=8.4 Hz, 2 H), 6.57 (d, J=3.6 Hz, 1 H), 3.35 (s, 3 H), 2.35 (s, 3 H).

Step 8:

A 50 mL vial was charged with a magnetic stir bar, 4-bromo-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one (0.281 g, 0.737 mmol), 1,4-dioxane (3.69 ml, 0.737 mmol), water (0.5 ml, 27.8 mmol), K₂CO₃ (0.306 g, 2.211 mmol), 4-(tertbutoxycarbonylamino)phenylboronic acid (0.227 g, 0.958 mmol), and Pd(PPh₃)₄ (0.085 g, 0.074 mmol). The vial was purged, placed under an atmosphere of nitrogen and heated to 95° C. with stirring for 12 h before being allowed to cool to room temperature. The reaction was then diluted with water (20 ml). A precipitate formed which was collected via vacuum filtration using a Buchner funnel. The solids were washed with additional water (2×25 mL), dried, and collected. This material was suspended in methanol (˜5 mL) and treated with KOH (200 mg). After 2 h the MeOH was removed in vacuo and the crude material was suspended in water (˜20 mL) and the resulting solids were collected via vacuum filtration using a Buchner funnel. The solids were washed with additional water, were collected, and dried in vacuo to afford tert-butyl 4-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenylcarbamate (362 mg, 0.907 mmol) as a light yellow solid. LCMS M/Z (M+H) 494.

Step 9:

A 50 mL round bottom flask was charged with a magnetic stir bar, tert-butyl 4-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenylcarbamate (350 mg, 1.031 mmol), MeOH (2.062 mL, 1.031 mmol), and HCl (1.031 mL, 4.12 mmol) (4N in dioxane). The reaction was then allowed to stir at rt for 4 h before being diluted with dioxane (25 mL). A precipitate formed which was collected via vacuum filtration using a Buchner funnel, washed with additional dioxane, and dried in vacuo to afford 4-(4-aminophenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one (188 mg, 0.786 mmol, 76% yield) as a white solid. LCMS M/Z (M+H) 240.

Step 10:

A 25 mL vial was charged with a magnetic stir bar, 4-(4-aminophenyl)-6-methyl-1Hpyrrolo[2,3-c]pyridin-7(6H)-one (0.038 g, 0.159 mmol), anhydrous DMF (0.794 ml, 0.159 mmol), DIPEA (0.139 ml, 0.794 mmol), 17-oxo-21-((3aS,4S,6aR)-2-oxohexahydro-1Hthieno[3,4-d]imidazol-4-yl)-4,7,10,13-tetraoxa-16-azahenicosan-1-oic acid (0.078 g, 0.159 mmol), and HATU (0.075 g, 0.199 mmol). The crude reaction mixture was directly purified via reverse phase HPLC to afford N-(4-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)-1-(5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamido)-3,6,9,12-tetraoxapentadecan-15-amide (31 mg, 0.041 mmol, 26.0% yield). LCMS M/Z (M+2H)/2 357.

Example 293

Synthesis of biotinylated probe compound (1001) for CECR2 assay described below.

Step 1:

2-methoxy-4-methyl-3-nitropyridine

A solution of 2-chloro-4-methyl-3-nitropyridine (250 g, 1.45 mol) in methanol (1.0 L) was added dropwise (2 h) to a stirred and cooled (0° C.) solution of sodium methoxide (250 g, 4.63 mol) in methanol (850 mL). After addition, the mixture was heated to reflux for 23 h, at which time TLC indicated the reaction had gone to completion. The mixture was concentrated under reduced pressure to a volume of approximately 900 mL, and quenched by addition of water (1.5 L). The resulting solid was collected by filtration, washed with water and dried under reduced pressure to give the title compound (250 g, 100% yield) as a brown solid. ¹H NMR (400 MHz, DMSO-d6): δ 8.22 (d, J=5.2 Hz, 1 H), 7.10 (d, J=5.6 Hz, 1 H), 3.92 (s, 3 H), 2.26 (s, 3 H).

Step 2:

5-bromo-2-methoxy-4-methyl-3-nitropyridine

Sodium acetate (365 g, 5.37 mol) was added to a stirred solution of 2-methoxy-4-methyl-3-nitropyridine (250 g, 1.49 mol) in acetic acid (1.5 L) at ambient temperature and then Br₂ (639 g, 4.00 mol) was added dropwise (30 min). After addition, the mixture was heated at 80° C. for 12 h, at which time TLC indicated the reaction had gone to completion. The mixture was cooled (0° C.) and quenched by sequential addition of 10% aqueous (1.5 L) and saturated aqueous Na₂SO₃ (1.5 L). The resulting solid was collected by filtration washed with water, and dried under reduced pressure to give the title compound (302 g, 82.2% yield) as a light yellow solid. ¹H NMR (400 MHz, DMSO-d6): δ 8.25 (s, 1 H), 3.94 (s, 3 H), 2.29 (s, 3 H).

Step 3:

(E)-2-(5-bromo-2-methoxy-3-nitro-4-pyridyl)-N,N-dimethyl-ethenamine

DMF-DMA (600 mL) was slowly added to a stirred and heated (80° C.) solution of 5-bromo-2-methoxy-4-methyl-3-nitropyridine (134 g, 0.54 mol) in DMF (1.1 L). After addition, the mixture was heated at 95° C. for 5 h, at which time TLC indicated the reaction had gone to completion. The mixture was cooled to room temperature and poured into ice-cold water (3 L). The resulting red solid was collected by filtration, washed with water, and dried under reduced pressure to give the title compound (167 g, 100% yield) as red solid. ¹H NMR (400 MHz, DMSO-d6): δ 8.24 (s, 1 H), 7.05 (d, J=13.6 Hz, 1 H), 7.05 (d, J=13.6 Hz, 1 H), 4.80 (d, J=13.2 Hz, 1 H), 3.88 (s, 3 H), 2.90 (s, 6 H).

Step 4:

4-bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine

A mixture of 2-(5-bromo-2-methoxy-3-nitropyridin-4-yl)-N,N-dimethylethenamine (50.0 g, 165 mmol), Fe (50.0 g, 893 mmol) and NH₄Cl (50.0 g, 943 mmol) in methanol/H₂O (1900/250 mL) was heated at reflux for 7 h, at which time LCMS indicated that the reaction had gone to completion. The mixture was filtered while hot and the cake was washed with methanol (3×200 mL). The combined filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (petroleum ether: Ethyl acetate=5:1) to give the crude product. This crude material was triturated with acetonitrile to give the title compound (37.4 g, 99.5% yield) as a light brown solid. LCMS M/Z (M+H) 226.7, 228.7.

Step 5:

4-bromo-7-methoxy-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridine

A solution of 4-bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine (34.3 g, 0.15 mol) in THF (700 mL) was added dropwise to a stirred and cooled (0° C.) solution of sodium hydride (60%, 19.2 g, 0.48 mol) in THF (700 mL). After addition, the mixture was stirred at room temperature for 1 h, and then cooled again to 0° C. Tosyl chloride (38.0 g, 0.20 mol) in THF (700 mL) was added dropwise and the resulting mixture was stirred at ambient temperature for 2 h. The reaction was quenched by addition of saturated aqueous ammonium chloride (1.0 L), and then extracted with ethyl acetate (3×600 mL). The combined organic extracts were dried over Na₂SO₄ and concentrated under reduced pressure. The residue was triturated with acetonitrile to give the title compound (51.2 g, 88.9% yield) as a brown solid. This crude material was used in the next step without further purification.

Step 6:

4-bromo-1-(p-tolylsulfonyl)-6H-pyrrolo[2,3-c]pyridin-7-one

HBr (40% aqueous, 1.1 L) was added to a solution of 4-bromo-7-methoxy-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridine (102.5 g, 0.27 mol) in ethanol (200 mL). After addition, the mixture was heated at 90° C. for 2 h, at which time TLC indicated that the reaction had gone to completion. The mixture was cooled to 0° C. and the resulting white solid was collected by filtration. This solid was washed with water and dried under vacuum to give the title compound (87.5 g, 88.6% yield) as a light brown solid. ¹H NMR (400 MHz, DMSO-d6): δ 11.48 (s, 1 H), 8.01 (d, J=3.6 Hz, 1 H), 8.90 (d, J=8.0 Hz, 2 H), 7.38 (d, J=8.0 Hz, 2 H), 7.32 (s, 1 H), 6.57 (d, J=3.2 Hz, 1 H), 2.34 (s, 3 H).

Step 7:

4-bromo-6-methyl-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridin-7-one

Methyl iodide (24.5 g, 172.8 mmol) was added dropwise to a stirred suspension of 4-bromo-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one (Intermediate A) (16.7 g, 45.5 mmol) and cesium carbonate (17.8 g, 54.6 mmol) in dioxane (250 mL). After addition, the reaction mixture was stirred at room temperature for 18 h, at which time LCMS indicated the reaction had gone to completion. The solvent was evaporated under reduced pressure, and the residue was diluted with water (200 mL). The mixture was extracted with EtOAc (3×200 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate=3:1) to give the title compound (14.0 g, 81.4% yield) as a brown solid. ¹H NMR (400 MHz, DMSO-d6): δ 8.03 (d, J=3.6 Hz, 1 H), 7.92 (d, J=8.4 Hz, 2 H), 7.78 (s, 1 H), 7.39 (d, J=8.4 Hz, 2 H), 6.57 (d, J=3.6 Hz, 1 H), 3.35 (s, 3 H), 2.35 (s, 3 H).

Step 8:

A 50 mL vial was charged with a magnetic stir bar, 4-bromo-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one (0.281 g, 0.737 mmol), 1,4-dioxane (3.69 ml, 0.737 mmol), water (0.5 ml, 27.8 mmol), K₂CO₃ (0.306 g, 2.211 mmol), 4-(tertbutoxycarbonylamino)phenylboronic acid (0.227 g, 0.958 mmol), and Pd(PPh₃)₄ (0.085 g, 0.074 mmol). The vial was purged, placed under an atmosphere of nitrogen and heated to 95° C. with stirring for 12 h before being allowed to cool to room temperature. The reaction was then diluted with water (20 ml). A precipitate formed which was collected via vacuum filtration using a Buchner funnel. The solids were washed with additional water (2×25 mL), dried, and collected. This material was suspended in methanol (˜5 mL) and treated with KOH (200 mg). After 2 h the MeOH was removed in vacuo and the crude material was suspended in water (˜20 mL) and the resulting solids were collected via vacuum filtration using a Buchner funnel. The solids were washed with additional water, were collected, and dried in vacuo to afford tert-butyl 4-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenylcarbamate (362 mg, 0.907 mmol) as a light yellow solid. LCMS M/Z (M+H) 494.

Step 9:

A 50 mL round bottom flask was charged with a magnetic stir bar, tert-butyl 4-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenylcarbamate (350 mg, 1.031 mmol), MeOH (2.062 mL, 1.031 mmol), and HCl (1.031 mL, 4.12 mmol) (4N in dioxane). The reaction was then allowed to stir at rt for 4 h before being diluted with dioxane (25 mL). A precipitate formed which was collected via vacuum filtration using a Buchner funnel, washed with additional dioxane, and dried in vacuo to afford 4-(4-aminophenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one (188 mg, 0.786 mmol, 76% yield) as a white solid. LCMS M/Z (M+H) 240.

Step 10:

A 25 mL vial was charged with a magnetic stir bar, 4-(4-aminophenyl)-6-methyl-1Hpyrrolo[2,3-c]pyridin-7(6H)-one (0.038 g, 0.159 mmol), anhydrous DMF (0.794 ml, 0.159 mmol), DIPEA (0.139 ml, 0.794 mmol), 17-oxo-21-((3aS,4S,6aR)-2-oxohexahydro-1Hthieno[3,4-d]imidazol-4-yl)-4,7,10,13-tetraoxa-16-azahenicosan-1-oic acid (0.078 g, 0.159 mmol), and HATU (0.075 g, 0.199 mmol). The crude reaction mixture was directly purified via reverse phase HPLC to afford N-(4-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)-1-(5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamido)-3,6,9,12-tetraoxapentadecan-1 5-amide (31 mg, 0.041 mmol, 26.0% yield). LCMS M/Z (M+2H)/2 357.

Example 294

The inhibitory activity of representative compounds against bromodomains can be evaluated using known methods or using one of the following assay protocols.

IC₅₀ Measurements for Inhibitors Using BRD4 AlphaLisa Binding Assay

His/Flag epitope tagged BRD4 BD1₄₂₋₁₆₈ was cloned, expressed, and purified to. BRD4 binding and inhibition was assessed by monitoring the engagement of biotinylated H4-tetraacetyl peptide (New England Peptide, NEP2069-1/13) with the target using the AlphaLisa technology (Perkin-Elmer). Specifically, in a 384 well ProxiPlate BRD4(BD1) (30 nM final) was combined with peptide (200 nM final) in 40 mM HEPES (pH 7.0), 40 mM NaCl, 1 mM DTT, 0.01% (w/v) BSA, and 0.008% (w/v) Brij-35 either in the presence of DMSO (final 1.2% DMSO) or compound dilution series in DMSO. After 20 minutes incubation at room temperature Alpha streptavidin donor beads and AlphaLisa anti-Flag acceptor beads were added to a final concentration of 10 ug/mL each. After three hours equilibration plates were read on an Envision instrument and IC₅₀s calculated using a four parameter non-linear curve fit.

IC₅₀ Measurements for Inhibitors Using BRD9 AlphaLisa Binding Assay

His/Flag epitope tagged BRD9₁₃₄₋₂₃₉ was cloned, expressed, and purified to homogeneity. BRD9 binding and inhibition was assessed by monitoring the engagement of biotinylated H4-tetraacetyl peptide (New England Peptide, NEP2069-11/13) with the target using the AlphaLisa technology (Perkin-Elmer). Specifically, in a 384 well ProxiPlate BRD9 (50 nM final) was combined with peptide (3 nM final) in 50 mM HEPES (pH 7.5), 150 mM NaCl, 1 mM TCEP, 0.01% (w/v) BSA, and 0.008% (w/v) Brij-35 either in the presence of DMSO (final 0.8% DMSO) or compound dilution series in DMSO. After 20 minutes incubation at room temperature AlphaLisa Streptavidin Acceptor Beads (Perkin-AL125C) and AlphaLisa Nickel donor beads (Perkin AS 10 ID) were added to a final concentration of 15 ug/mL each. After ninety minutes of equilibration in the dark, the plates were read on an Envision instrument and IC₅₀s calculated using a four parameter non-linear curve fit.

IC₅₀ Measurements for Inhibitors Using TAF1-BD2 TR-FRET Binding Assay

His/Flag epitope tagged TAF1-BD2₁₅₀₄₋₁₆₃₅ was cloned, expressed, and purified to homogeneity. TAF1-BD2 binding and inhibition was assessed by monitoring the engagement of a biotinylated small molecule compound 1000 (Example 292) with the target using the TR-FRET assay technology (Perkin-Elmer). Specifically, in a 384 well ProxiPlate TAF1-BD2 (6 nM final) was combined with biotin-ligand (50 nM final) in 50 mM HEPES (pH 7.5), 50 mM NaCl, 1 mM TCEP, 0.01% (w/v) BSA, and 0.008% (w/v) Brij-35 either in the presence of DMSO (final 0.2% DMSO) or compound dilution series in DMSO. After 10 minutes incubation at room temperature, a mixture Eu-W1024 Anti-6×His antibody (Perkin Elmer AD0110) and SureLight™ Allophycocyanin-Streptavidin (APC-SA, Perkin Elmer CR130-100) were added to a final concentrations of 0.2 nMolar antibody and 25 nMolar APC-SA, respectively. After twenty minutes of equilibration, the plates were read on an Envision instrument and IC₅₀s calculated using a four parameter non-linear curve fit. Novel compound 1000 and the TAF1-BD2 TR-FRET Binding Assay described above represent additional embodiments of the invention.

IC50 Measurements for Inhibitors Using CECR2 TR-FRET Binding Assay

His/Flag epitope tagged CECR2₄₂₄₋₅₃₈ was cloned, expressed, and purified to homogeneity. CECR2 binding and inhibition was assessed by monitoring the engagement of a biotinylated small molecule compound 1001 (Example 293) with the target using the TR-FRET assay technology (Perkin-Elmer). Specifically, in a 384 well ProxiPlate CECR2 (1.5 nM final) was combined with biotin-ligand (25 nM final) in 50 mM HEPES (pH 7.5), 50 mM NaCl, 1 mM TCEP, 0.01% (w/v) BSA, and 0.008% (w/v) Brij-35 either in the presence of DMSO (final 0.2% DMSO) or compound dilution series in DMSO. After 15 minutes incubation at room temperature, a mixture Eu-W1024 Anti-6×His antibody (Perkin Elmer AD0110) and SureLight™ Allophycocyanin-Streptavidin (APC-SA, Perkin Elmer CR130-100) were added to a final concentrations of 0.2 nMolar antibody and 12.5 nMolar APC-SA, respectively. After forty minutes of equilibration, the plates were read on an Envision instrument and IC₅₀s calculated using a four parameter non-linear curve fit. Novel compound 1001 and the CECR2 TR-FRET Binding Assay described above represent additional embodiments of the invention.

Data for representative compounds of formula (I) from the four assays described above is provided in the following table.

Example Assay IC50 (uM) 8 BRD4 4.9 28 BRD4 19 31 BRD4 17 32 BRD4 9.8 46 BRD4 6.4 50 BRD4 16 55 BRD4 9.5 57 BRD4 4.1 64 BRD4 8.0 92 BRD4 8.4 93 BRD4 2.9 94 BRD4 3.1 95 BRD4 11 96 BRD4 5.0 101 BRD4 17 105 BRD4 19 116 BRD4 4.3 117 BRD4 4.0 119 BRD4 1.2 123 BRD4 11 126 BRD4 3.2 127 BRD4 1.2 128 BRD4 16 132 BRD4 13 179 BRD4 2.1 198 BRD4 1.1 215 BRD4 3.8 222 BRD4 16 256 BRD4 3.8 258 BRD4 0.80 261 BRD4 2.7 262 BRD4 3.3 265 BRD4 5.3 1 BRD9 3.0 3 BRD9 3.5 5 BRD9 0.79 6 BRD9 1.5 7 BRD9 0.99 9 BRD9 0.92 11 BRD9 5.4 12 BRD9 0.84 18 BRD9 2.1 19 BRD9 0.075 22 BRD9 7.3 33 BRD9 5.4 34 BRD9 2.2 35 BRD9 11 38 BRD9 8.0 39 BRD9 19 45 BRD9 6.1 85 BRD9 0.57 86 BRD9 0.16 87 BRD9 1.0 88 BRD9 1.5 89 BRD9 4.1 90 BRD9 0.30 91 BRD9 0.20 97 BRD9 0.49 98 BRD9 0.55 102 BRD9 0.86 103 BRD9 0.49 104 BRD9 0.98 106 BRD9 0.24 107 BRD9 3.4 108 BRD9 0.20 109 BRD9 0.27 110 BRD9 0.85 111 BRD9 0.24 112 BRD9 0.46 114 BRD9 0.073 115 BRD9 0.64 118 BRD9 0.24 120 BRD9 0.44 121 BRD9 0.10 122 BRD9 2.2 124 BRD9 2.9 125 BRD9 0.13 129 BRD9 0.22 131 BRD9 1.6 134 BRD9 0.28 136 BRD9 0.40 138 BRD9 0.31 146 BRD9 1.6 159 BRD9 4.3 161 BRD9 2.9 190 BRD9 15 217 BRD9 4.7 248 BRD9 3.3 257 BRD9 0.18 259 BRD9 0.60 260 BRD9 0.18 263 BRD9 0.48 264 BRD9 0.44 2 CECR2 14 21 CECR2 0.89 23 CECR2 2.1 26 CECR2 3.2 29 CECR2 1.8 30 CECR2 3.8 37 CECR2 3.1 41 CECR2 0.77 59 CECR2 0.89 60 CECR2 10.3 61 CECR2 1.0 62 CECR2 1.5 65 CECR2 1.4 66 CECR2 2.4 67 CECR2 1.8 68 CECR2 3.0 69 CECR2 0.45 72 CECR2 2.2 73 CECR2 2.5 74 CECR2 5.9 75 CECR2 4.8 76 CECR2 0.35 77 CECR2 2.7 78 CECR2 9.9 79 CECR2 5.1 80 CECR2 0.51 113 CECR2 0.31 139 CECR2 0.24 140 CECR2 0.34 141 CECR2 0.39 142 CECR2 0.29 143 CECR2 0.40 144 CECR2 0.43 145 CECR2 0.41 147 CECR2 0.51 158 CECR2 0.79 160 CECR2 0.18 162 CECR2 0.12 163 CECR2 0.091 164 CECR2 0.21 165 CECR2 0.087 167 CECR2 0.12 168 CECR2 0.042 169 CECR2 0.023 170 CECR2 0.042 172 CECR2 1.0 173 CECR2 0.99 174 CECR2 0.59 175 CECR2 0.76 176 CECR2 0.93 177 CECR2 0.69 178 CECR2 0.74 181 CECR2 0.73 182 CECR2 0.41 183 CECR2 0.49 184 CECR2 0.47 185 CECR2 0.91 186 CECR2 0.44 187 CECR2 0.79 188 CECR2 2.0 189 CECR2 1.0 191 CECR2 0.59 192 CECR2 1.4 197 CECR2 0.73 201 CECR2 0.99 202 CECR2 1.3 203 CECR2 1.1 204 CECR2 1.1 205 CECR2 0.71 206 CECR2 0.37 207 CECR2 0.81 208 CECR2 1.2 211 CECR2 2.2 212 CECR2 1.7 213 CECR2 0.71 214 CECR2 0.66 216 CECR2 1.2 218 CECR2 0.77 220 CECR2 1.1 221 CECR2 0.67 223 CECR2 0.97 224 CECR2 0.78 225 CECR2 1.4 226 CECR2 0.70 227 CECR2 2.0 229 CECR2 0.64 230 CECR2 0.79 232 CECR2 1.2 233 CECR2 0.77 234 CECR2 1.0 239 CECR2 2.3 241 CECR2 1.1 242 CECR2 1.4 243 CECR2 2.0 244 CECR2 19 249 CECR2 4.8 251 CECR2 6.2 253 CECR2 0.98 254 CECR2 0.70 266 CECR2 0.030 267 CECR2 0.017 268 CECR2 0.023 269 CECR2 0.033 270 CECR2 0.018 271 CECR2 0.011 272 CECR2 0.035 273 CECR2 4.90 274 CECR2 0.074 275 CECR2 0.11 276 CECR2 0.038 277 CECR2 0.053 278 CECR2 0.057 279 CECR2 0.012 280 CECR2 0.049 281 CECR2 0.032 282 CECR2 0.067 283 CECR2 0.044 284 CECR2 0.053 285 CECR2 0.15 286 CECR2 0.041 287 CECR2 0.084 288 CECR2 0.041 289 CECR2 0.045 290 CECR2 0.050 291 CECR2 0.140 4 TAF-1 0.32 10 TAF-1 4.7 14 TAF-1 3.7 15 TAF-1 0.97 16 TAF-1 6.0 17 TAF-1 3.6 20 TAF-1 1.5 24 TAF-1 0.15 25 TAF-1 0.69 27 TAF-1 6.9 36 TAF-1 1.7 40 TAF-1 0.069 42 TAF-1 0.21 43 TAF-1 0.72 44 TAF-1 0.34 47 TAF-1 2.3 48 TAF-1 1.5 49 TAF-1 3.9 51 TAF-1 4.4 52 TAF-1 7.1 53 TAF-1 8.2 54 TAF-1 2.9 56 TAF-1 2.5 58 TAF-1 1.5 63 TAF-1 4.7 70 TAF-1 6.4 71 TAF-1 3.0 81 TAF-1 0.71 82 TAF-1 7.0 83 TAF-1 0.67 84 TAF-1 5.7 100 TAF-1 1.7 130 TAF-1 1.2 133 TAF-1 0.85 135 TAF-1 1.3 137 TAF-1 0.51 148 TAF-1 0.44 149 TAF-1 0.32 150 TAF-1 0.36 151 TAF-1 0.55 152 TAF-1 0.57 153 TAF-1 0.49 154 TAF-1 0.53 155 TAF-1 0.33 156 TAF-1 0.99 157 TAF-1 1.6 166 TAF-1 2.1 171 TAF-1 0.26 180 TAF-1 0.16 193 TAF-1 1.6 199 TAF-1 18 200 TAF-1 8.0 209 TAF-1 0.58 210 TAF-1 5.3 219 TAF-1 3.6 228 TAF-1 3.3 231 TAF-1 9.9 235 TAF-1 9.9 236 TAF-1 14 238 TAF-1 2.1 240 TAF-1 3.4 250 TAF-1 14 252 TAF-1 5.0 255 TAF-1 4.8

While a number of embodiments have been described, these examples may be altered to provide other embodiments that utilize the compounds and methods described herein. Therefore, the scope of this invention is to be defined by the appended claims rather than by the specific embodiments that have been represented by way of example. 

We claim:
 1. A compound of formula (I):

or a salt thereof, wherein: R¹ is H, C₁₋₁₂alkyl, C₂₋₁₂alkenyl, C₂₋₁₂alkynyl, or carbocyclyl, wherein each C₁₋₁₂alkyl, C₂₋₁₂alkenyl, C₂₋₁₂alkynyl, and carbocyclyl of R¹ is optionally substituted with one or more groups R^(a); R² is H, C₁₋₁₂alkyl, C₂₋₁₂alkenyl, C₂₋₁₂alkynyl, or C₃₋₈cycloalkyl, wherein each C₁₋₁₂alkyl, C₂₋₁₂alkenyl, C₂₋₁₂alkynyl, and C₃₋₈cycloalkyl of R² is optionally substituted with one or more groups R^(b); and each R^(a) is independently selected from the group consisting oxo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, carbocyclyl, heterocyclyl, —F, —Cl, —Br, —I, —NO₂, —N(R^(v))₂, —CN, —C(O)—N(R^(v))₂, —S(O)—N(R^(v))₂, —S(O)₂—N(R^(v))₂, —O—R^(v), —S—R^(v), —O—C(O)—R^(v), —O—C(O)—O—R^(v), —C(O)—R^(v), —C(O)—O—R^(v), —S(O)—R^(v), —S(O)₂—R^(v), —O—C(O)—N(R^(v))₂, —N(R^(v))—C(O)—OR^(v), —N(R^(v))—C(O)—N(R^(v))₂, —N(R^(v))—C(O)—R^(v), —N(R^(v))—S(O)—R^(v), —N(R^(v))—S(O)₂—R^(v), —N(R^(v))—S(O)—N(R^(v))₂, and —N(R^(v))—S(O)₂—N(R^(v))₂, wherein any C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, carbocyclyl, and heterocyclyl, is optionally substituted with one or more groups independently selected from the group consisting of oxo, halo, —NO₂, —N(R^(v))₂, —CN, —C(O)—N(R^(v))₂, —S(O)—N(R^(v))₂, —S(O)₂—N(R^(v))₂, —O—R^(v), —S—R^(v), —O—C(O)—R^(v), —C(O)—R^(v), —C(O)—O—R^(v), —S(O)—R^(v), —S(O)₂—R^(v), —C(O)—N(R^(v))₂, —N(R^(v))—C(O)—R^(v), —N(R^(v))—S(O)—R^(v), —N(R^(v))—S(O)₂—R^(v) and C₁₋₆alkyl that is optionally substituted with one or more groups independently selected from the group consisting of oxo and halo; each R^(b) is independently selected from the group consisting of oxo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, carbocyclyl, heterocyclyl, —F, —Cl, —Br, —I, —NO₂, —N(R^(w))₂, —CN, —C(O)—N(R^(w))₂, —S(O)—N(R^(w))₂, —S(O)₂—N(R^(w))₂, —O—R^(w), —S—R^(w), —O—C(O)—R^(w), —O—C(O)—O—R^(w), —C(O)—R^(w), —C(O)—O—R^(w), —S(O)—R^(w), —S(O)₂—R^(w), —O—C(O)—N(R^(w))₂, —N(R^(w))—C(O)—OR^(w), —N(R^(w))—C(O)—N(R^(w))₂, —N(R^(w))—C(O)—R^(w), —N(R^(w))—S(O)—R^(w), —N(R^(w))—S(O)₂—R^(w), —N(R^(w))—S(O)—N(R^(w))₂, and —N(R^(w))—S(O)₂—N(R^(w))₂, wherein any C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from the group consisting of oxo, halo, —NO₂, —N(R^(w))₂, —CN, —C(O)—N(R^(w))₂, —S(O)—N(R^(w))₂, —S(O)₂—N(R^(w))₂, —O—R^(w), —S—R^(w), —O—C(O)—R^(w), —C(O)—R^(w), —C(O)—O—R^(w), —S(O)—R^(w), —S(O)₂—R^(w), —C(O)—N(R^(w))₂, —N(R^(w))—C(O)—R^(w), —N(R^(w))—S(O)—R^(w), —N(R^(w))—S(O)₂—R^(w) and C₁₋₆alkyl that is optionally substituted with one or more groups independently selected from the group consisting of oxo and halo; each R^(c) and R^(d) is independently selected from the group consisting of hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl, wherein each C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more substituent groups independently selected from the group consisting of oxo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, heterocyclyl, —F, —Cl, —Br, —I, —NO₂, —N(R^(v))₂, —CN, —C(O)—N(R^(h))₂, —S(O)—N(R^(h))₂, —S(O)₂—N(R^(h))₂, —O—R^(h), —S—R^(h), —O—C(O)—R^(h), —O—C(O)—O—R^(h), —C(O)—R^(h), —C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h), —O—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—OR^(h), —N(R^(h))—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)—R^(h), —N(R^(h))—S(O)₂—R^(h), —N(R^(h))—S(O)—N(R^(h))₂, and —N(R^(h))—S(O)₂—N(R^(h))₂, wherein any C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl of the substituent groups, is optionally substituted with one or more groups independently selected from the group consisting of oxo, carbocyclyl, heterocyclyl, halo, —NO₂, —N(R^(h))₂, —CN, —C(O)—N(R^(h))₂, —S(O)—N(R^(h))₂, —S(O)₂—N(R^(h))₂, —O—R^(h), —S—R^(h), —O—C(O)—R^(h), —C(O)—R^(h), —C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h), —C(O)—N(R^(h))₂, —N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)—R^(h), N(R^(h))—S(O)₂—R^(h), and C₁₋₆alkyl, which heterocyclyl, carbocyclyl and C₁₋₆alkyl are optionally substituted with one or more groups independently selected from the group consisting of oxo, halo, C₁₋₆alkyl, cyano, —O—R^(h), heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C₁₋₆alkyl; or R^(c) and R^(d) are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from the group consisting of oxo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, heterocyclyl, —F, —Cl, —Br, —I, —NO₂, —N(R^(v))₂, —CN, —C(O)—N(R^(h))₂, —S(O)—N(R^(h))₂, —S(O)₂—N(R^(h))₂, —O—R^(h), —S—R^(h), —O—C(O)—R^(h), —O—C(O)—O—R^(h), —C(O)—R^(h), —C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h), —O—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—OR^(h), —N(R^(h))—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)—R^(h), —N(R^(h))—S(O)₂—R^(h), —N(R^(h))—S(O)—N(R^(h))₂, and —N(R^(h))—S(O)₂—N(R^(h))₂, wherein any C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from the group consisting of C₁₋₆alkyl, carbocyclyl, heterocyclyl, —F, —Cl, —Br, —I, —NO₂, —N(R^(h))₂, —CN, —C(O)—N(R^(h))₂, —S(O)—N(R^(h))₂, —S(O)₂—N(R^(h))₂, —O—R^(h), —S—R^(h), —O—C(O)—R^(h), —O—C(O)—O—R^(h), —C(O)—R^(h), —C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h), —O—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—OR^(h), —N(R^(h))—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)—R^(h), —N(R^(h))—S(O)₂—R^(h), —N(R^(h))—S(O)—N(R^(h))₂, and —N(R^(h))—S(O)₂—N(R^(h))₂, which C₁₋₆alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halo and C₁₋₆alkyl; each R^(h) is independently selected from hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl, wherein each C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from the group consisting of oxo, halo, amino, hydroxyl, carbocyclyl, heterocyclyl, and C₁-C₆ alkyl that is optionally substituted with one or more groups independently selected from the group consisting of oxo and halo; or two R^(h) are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from the group consisting of oxo, halo and C₁₋₃ alkyl that is optionally substituted with one or more groups independently selected from the group consisting of oxo and halo; each R^(v) is independently selected from the group consisting of hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl, wherein each C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from the group consisting of oxo, halo, amino, hydroxyl, and C₁-C₆ alkyl that is optionally substituted with one or more groups independently selected from the group consisting of oxo and halo; or two R^(v) are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from the group consisting of oxo, halo and C₁₋₃alkyl that is optionally substituted with one or more groups independently selected from the group consisting of oxo and halo; and each R^(w) is independently selected from the group consisting of hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl, wherein each C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from the group consisting of oxo, halo, amino, hydroxyl, and C₁-C₆ alkyl that is optionally substituted with one or more groups independently selected from the group consisting of oxo and halo; or two R^(w) are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from the group consisting of oxo, halo and C₁₋₃alkyl that is optionally substituted with one or more groups independently selected from the group consisting of oxo and halo.
 2. The compound of claim 1 wherein R¹ is C₁₋₆alkyl or C₂₋₆alkenyl, wherein each C₁₋₆alkyl and, C₂₋₆alkenyl is optionally substituted with one or more groups R^(a).
 3. The compound of claim 1 wherein R¹ is C₁₋₆alkyl or C₂₋₆alkenyl, wherein each C₁₋₆alkyl and C₂₋₆alkenyl is optionally substituted with one or more groups independently selected from carbocyclyl, —F, —Cl, —O—R^(v), —O—C(O)—R^(v), —C(O)—R^(v), and —C(O)—O—R^(v).
 4. The compound of claim 1 wherein R¹ is C₁₋₆alkyl or C₂₋₆alkenyl, wherein each C₁₋₆alkyl and C₂₋₆alkenyl is optionally substituted with one or more groups independently selected from C₃₋₆cycloalkyl.
 5. The compound of claim 1 wherein R¹ is methyl, butyl, 2-propenyl, 2-buten-1-yl, 3-buten-1-yl or 2-cyclopropylethyl.
 6. The compound of claim 1 wherein R² is H or C₁₋₆alkyl wherein each C₁₋₆alkyl is optionally substituted with one or more groups R^(b).
 7. The compound of claim 1 wherein R^(c) is hydrogen, C₁₋₆alkyl, or C₃₋₈cycloalkyl, wherein each C₁₋₆alkyl and C₃₋₈cycloalkyl is optionally substituted with one or more substituent groups independently selected from —O—R^(h).
 8. The compound of claim 1 wherein R^(c) is hydrogen, methyl, ethyl, cyclopropyl, cyclobutyl, or 2-methoxyethyl.
 9. The compound of claim 1 wherein R^(d) is C₁₋₆alkyl that is optionally substituted with one or more substituent groups independently selected from the group consisting of oxo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, heterocyclyl, —F, —Cl, —Br, —I, —NO₂, —N(R^(v))₂, —CN, —C(O)—N(R^(h))₂, —S(O)—N(R^(h))₂, —S(O)₂—N(R^(h))₂, —O—R^(h), —S—R^(h), —O—C(O)—R^(h), —O—C(O)—O—R^(h), —C(O)—R^(h), —C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h), —O—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—OR^(h), —N(R^(h))—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)—R^(h), —N(R^(h))—S(O)₂—R^(h), —N(R^(h))—S(O)—N(R^(h))₂, and —N(R^(h))—S(O)₂—N(R^(h))₂, wherein any C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl of the substituent groups is optionally substituted with one or more groups independently selected from the group consisting of oxo, carbocyclyl, heterocyclyl, halo, —NO₂, —N(R^(h))₂, —CN, —C(O)—N(R^(h))₂, —S(O)—N(R^(h))₂, —S(O)₂—N(R^(h))₂, —O—R^(h), —S—R^(h), —O—C(O)—R^(h), —C(O)—R^(h), —C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h), —C(O)—N(R^(h))₂, —N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)—R^(h), N(R^(h))—S(O)₂—R^(h), and C₁₋₆alkyl, which heterocyclyl, carbocyclyl and C₁₋₆alkyl are optionally substituted with one or more groups independently selected from the group consisting of oxo, halo, C₁₋₆alkyl, cyano, —O—R^(h), heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from the group consisting of halo and C₁₋₆alkyl.
 10. The compound of claim 1 wherein R^(d) is carbocyclyl that is optionally substituted with one or more substituent groups independently selected from the group consisting of oxo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, heterocyclyl, —F, —Cl, —Br, —I, —NO₂, —N(R^(v))₂, —CN, —C(O)—N(R^(h))₂, —S(O)—N(R^(h))₂, —S(O)₂—N(R^(h))₂, —O—R^(h), —S—R^(h), —O—C(O)—R^(h), —O—C(O)—O—R^(h), —C(O)—R^(h), —C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h), —O—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—OR^(h), —N(R^(h))—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)—R^(h), —N(R^(h))—S(O)₂—R^(h), —N(R^(h))—S(O)—N(R^(h))₂, and —N(R^(h))—S(O)₂—N(R^(h))₂, wherein any C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl of the substituent groups is optionally substituted with one or more groups independently selected from the group consisting of oxo, carbocyclyl, heterocyclyl, halo, —NO₂, —N(R^(h))₂, —CN, —C(O)—N(R^(h))₂, —S(O)—N(R^(h))₂, —S(O)₂—N(R^(h))₂, —O—R^(h), —S—R^(h), —O—C(O)—R^(h), —C(O)—R^(h), —C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h), —C(O)—N(R^(h))₂, —N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)—R^(h), N(R^(h))—S(O)₂—R^(h), and C₁₋₆alkyl, which heterocyclyl, carbocyclyl and C₁₋₆alkyl are optionally substituted with one or more groups independently selected from the group consisting of oxo, halo, C₁₋₆alkyl, cyano, —O—R^(h), heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from the group consisting of halo and C₁₋₆alkyl.
 11. The compound of claim 1 wherein R^(d) is heterocyclyl that is optionally substituted with one or more substituent groups independently selected from the group consisting of oxo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, heterocyclyl, —F, —Cl, —Br, —I, —NO₂, —N(R^(v))₂, —CN, —C(O)—N(R^(h))₂, —S(O)—N(R^(h))₂, —S(O)₂—N(R^(h))₂, —O—R^(h), —S—R^(h), —O—C(O)—R^(h), —O—C(O)—O—R^(h), —C(O)—R^(h), —C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h), —O—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—OR^(h), —N(R^(h))—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)—R^(h), —N(R^(h))—S(O)₂—R^(h), —N(R^(h))—S(O)—N(R^(h))₂, and —N(R^(h))—S(O)₂—N(R^(h))₂, wherein any C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl of the substituent groups is optionally substituted with one or more groups independently selected from the group consisting of oxo, carbocyclyl, heterocyclyl, halo, —NO₂, —N(R^(h))₂, —CN, —C(O)—N(R^(h))₂, —S(O)—N(R^(h))₂, —S(O)₂—N(R^(h))₂, —O—R^(h), —S—R^(h), —O—C(O)—R^(h), —C(O)—R^(h), —C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h), —C(O)—N(R^(h))₂, —N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)—R^(h), N(R^(h))—S(O)₂—R^(h), and C₁₋₆alkyl, which heterocyclyl, carbocyclyl and C₁₋₆alkyl are optionally substituted with one or more groups independently selected from the group consisting of oxo, halo, C₁₋₆alkyl, cyano, —O—R^(h), heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo and C₁₋₆alkyl.
 12. The compound of claim 1 wherein R^(c) and R^(d) are taken together with the nitrogen to which they are attached to form a 5-6 membered monocyclic heterocyclyl or a 8-12 membered bicyclic heterocyclyl, wherein the monocyclic or bicyclic heterocyclyl is optionally substituted with one or more groups independently selected from the group consisting of oxo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, heterocyclyl, —F, —Cl, —Br, —I, —NO₂, —N(R^(v))₂, —CN, —C(O)—N(R^(h))₂, —S(O)—N(R^(h))₂, —S(O)₂—N(R^(h))₂, —O—R^(h), —S—R^(h), —O—C(O)—R^(h), —O—C(O)—O—R^(h), —C(O)—R^(h), —C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h), —O—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—OR^(h), —N(R^(h))—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)—R^(h), —N(R^(h))—S(O)₂—R^(h), —N(R^(h))—S(O)—N(R^(h))₂, and —N(R^(h))—S(O)₂—N(R^(h))₂, wherein any C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from the group consisting of C₁₋₆alkyl, carbocyclyl, heterocyclyl, —F, —Cl, —Br, —I, —NO₂, —N(R^(h))₂, —CN, —C(O)—N(R^(h))₂, —S(O)—N(R^(h))₂, —S(O)₂—N(R^(h))₂, —O—R^(h), —S—R^(h), —O—C(O)—R^(h), —O—C(O)—O—R^(h), —C(O)—R^(h), —C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h), —O—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—OR^(h), —N(R^(h))—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)—R^(h), —N(R^(h))—S(O)₂—R^(h), —N(R^(h))—S(O)—N(R^(h))₂, and —N(R^(h))—S(O)₂—N(R^(h))₂, which C₁₋₆alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more groups independently selected from halo and C₁₋₆alkyl.
 13. The compound of claim 1 wherein —C(═O)NR^(c)R^(d) is selected from the group consisting of:


14. The compound of claim 1 that is selected from the group consisting of:

or a salt thereof.
 15. A composition comprising a compound of formula (I) as described in claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, carrier, or vehicle. 